Alanine 2, 6-dialkoxyphenyl ester derivatives as hypnotics

ABSTRACT

The present invention relates to alanine 2,6-dialkoxyphenyl ester derivatives having the general formula I, Formula (I) wherein R 1  is (C 1-3 )alkyloxy, (C 1-3 )alkyloxy(C 1-3 )alkyl, (C 1-3 )alkylthio, (C 1-3 )alkylthio(C 1-3 )alkyl, (C 1-3 )alkylsulfinyl, (C 1-3 )alkylsulfinyl(C 1-3 )alkyl, (C 1-3 )alkylsulfonyl, (C 1-3 )alkylsulfonyl(C 1-3 )alkyl, (C 1-3 )alkyloxycarbonyl,   (CH 2 ) n —CO—NR 8 R 9? or   (CH2) n —NR 8 R 9?; n is 0, 1 or 2; R 2  is hydrogen or   (C 1-3?)alkyl; R 3  is (C 1-3 )alkyl or    (C 1-3 )alkyloxy(C 1-3?)alkyl; R 4  is (C 1-3 )alkyloxy(C 1-3 )alkyl; or R 3  and R 4  form together with the nitrogen atom to which they are bound a 5-, 6-, or 7-membered ring, optionally containing a further heteroatom selected from O and S, and which ring may optionally contain a double bond and be optionally substituted with (C 1-3 )alkyl or (C 1-3 )alkyloxy; R 5  and R 6  are independently (C 1-3 )alkyl; R 7  is hydrogen, (C 1-3 )alkyl, (C 1-3 )alkyloxy or (C 2-3 )alkenyl; R 8  and R 9  are independently (C 1-3 )alkyl; or R 8  and R 9  form together with the nitrogen atom to which they are bound a 5-, 6-, or 7-membered, optionally containing a further heteroatom selected from O and S, and which ring may optionally contain a double bond; or a pharmaceutically acceptable salt thereof. The invention also relates to pharmaceutical compositions comprising said derivatives, and to the use of these alanine 2,6-dialkoxyphenyl ester derivatives as hypnotics for the induction and maintenance of general anaesthesia.

[0001] The invention relates to alanine 2,6-dialkoxyphenyl esterderivatives, to pharmaceutical compositions containing the same, as wellas to the use of these alanine 2,6-dialkoxyphenyl ester derivatives ashypnotics for the induction and maintenance of general anaesthesia.

[0002] It has been reported (G. Brancaccio and A. Larizza, II Farmaco1964, 19, 986-1002) that alanine 2,6-dialkoxyphenyl ester derivatives,wherein the amino group is either dialkylated or is part of anheterocyclic system (GB 1,102,011: Richardson-Merrell S.p.A.), possesslocal anaesthetic activity, with piperazinyl derivatives proving themost active. In GB 1,160,468 (May & Baker Ltd.) an alanine2,6-dialkoxyphenyl ester derivative wherein the amino group is part of amorpholinyl ring, i.e. 2,6-dimethoxyphenyl 2-morpholinopropionate, isdisclosed as an intravenous general anaesthetic having a short durationof activity with rapid, smooth recovery. The hypnotic properties of thiscompound are attained at rather high dose levels and consequently thereexists a need for water soluble general anaesthetics with improvedpotency.

[0003] The present invention provides alanine 2,6-dialkoxyphenyl esterderivatives having the general formula I

[0004] wherein

[0005] R₁ is (C₁₋₃)alkyloxy, (C₁₋₃)alkyloxy(C₁₋₃)alkyl, (C₁₋₃)alkylthio,(C₁₋₃)alkylthio(C₁₋₃)-alkyl, (C₁₋₃)alkylsulfinyl,(C₁₋₃)alkylsulfinyl(C₁₋₃)alkyl, (C₁₋₃)alkylsulfonyl,(C₁₋₃)alkylsulfonyl(C₁₋₃)alkyl, (C₁₋₃)alkyloxycarbonyl,(CH₂)_(n)—CO—NR₈R₉ or (CH₂)_(n)—NR₈R₉;

[0006] n is 0, 1 or 2;

[0007] R₂ is hydrogen or (C₁₋₃)alkyl;

[0008] R₃ is (C₁₋₃)alkyl or (C₁₋₃)alkyloxy(C₁₃)alkyl;

[0009] R₄ is (C₁₋₃)alkyloxy(C₁ ₃)alkyl; or

[0010] R₃ and R₄ form together with the nitrogen atom to which they arebound a 5-, 6-, or 7-membered ring, optionally containing a furtherheteroatom selected from O and S, and which ring may optionally containa double bond and be optionally substituted with (C₁₋₃)alkyl or(C₁₋₃)alkyloxy;

[0011] R₅ and R₆ are independently (C₁₋₃)alkyl;

[0012] R₇ is hydrogen, (C₁₋₃)alkyl, (C₁₋₃)alkyloxy or (C₂₋₃)alkenyl;

[0013] R₈ and R₉ are independently (C₁₋₃)alkyl; or

[0014] R₈ and R₉ form together with the nitrogen atom to which they arebound a 5-, 6-, or 7-membered, optionally containing a furtherheteroatom selected from O and S, and which ring may optionally containa double bond; or a pharmaceutically acceptable salt thereof.

[0015] The alanine 2,6-dialkoxyphenyl ester derivatives of formula I,having an amino group which is either dialkylated or is part of aheterocyclic ring system, were found to be potent intravenous hypnoticswith quick onset, and a short duration of action with rapid, smoothrecovery. Many of the compounds have the additional advantage of beinghighly water soluble.

[0016] The term (C₁₋₃)alkyl, as used in the definition of formula I,means a branched or unbranched alkyl goup having. 1-3 carbon atoms, liken-propyl, isopropyl, ethyl and methyl.

[0017] In the term (C₁₋₃)alkyloxy as used in formula I, (C₁₋₃)alkyl hasthe meaning as previously given, preferably methyl.

[0018] The term (C₂₋₃)alkenyl means an alkenyl group having 2 or 3atoms, such as propen-2-yl (allyl), propen-1-yl or ethenyl (vinyl).Alkenyl groups having 3 carbon atoms may be in the E- or Z-form, or amixture thereof.

[0019] In the definition of Formula I R₃ and R₄ may form together withthe nitrogen atom to which they are bound a 5-, 6-, or 7-membered ring,optionally containing a further heteroatom selected from O and S, andwhich ring may optionally contain a double bond and be optionallysubstituted with (C₁₋₃)alkyl or (C₁₋₃)alkyloxy. Examples of such ringsystems are hexahydro-1,4-oxazepine (homomorpholine), morpholine,thiomorpholine, hexahydroazepine (homopiperidine), pyrrolidine,piperidine, 1,2,3,6-tetrahydropyridine, 4-methoxypiperidine,2,2-dimethylmorpholine, 2,2-dimethylthiomorpholine,1,2,3,4-tetrahydroisoquinoline, 2-methylmorpholine, 2-ethylmorpholine,2-isopropylmorpholine and the like. Preferred ring systems formed by R₃and R₄ are hexahydro-1,4-oxazepine, morpholine and thiomorpholine.

[0020] In the definition of Formula I R₁, can be (CH₂)_(n)—CO—NR₈R₉ or(CH₂)_(n)—NR₈R₉, wherein n is 0, 1 or 2, and wherein R₈ and R₉ may formtogether with the nitrogen atom to which they are bound a 5-, 6-, or7-membered, optionally containing a further heteroatom selected from Oand S, and which ring may optionally contain a double bond. Examples ofsuch ring systems are hexahydro-1,4-oxazepine, morpholine,thiomorpholine, pyrrolidine, piperidine, 1,2,3,6-tetrahydropyridine,2,2-dimethylmorpholine and the like.

[0021] Preferred alanine 2,6-dialkoxyphenyl ester derivatives of theinvention correspond to compounds having formula I wherein R₅ and R₆ ismethyl. More preferred are the derivatives wherein R₃ and R₄ formtogether with the nitrogen atom to which they are bound form a 5-, 6- or7-membered ring. Examples of such ring systems, as well as the preferredones are as given above.

[0022] The compounds of formula I and their salts contain at least onecentre of chirality, i.e. at the α-carbon atom, and exist therefore asstereoisomers, including enantiomers and, when appropriate,diastereomers. The present invention includes the aforementionedstereoisomers within its scope and each of the individual R and Senantiomers of the compounds of formula I and their salts, substantiallyfree, i.e. associated with less than 5%, preferably less than 2%, inparticular less than 1% of the other enantiomer, and mixtures of suchenantiomers in any proportions including the, racemic mixturescontaining substantially equal amounts or the two enantiomers.

[0023] Preferred are the alanine 2,6-dialkoxyphenyl ester derivatives offormula I wherein the configuration at the α-carbon atom is that of theR-enantiomer. Particular preferred compounds according to the invention,which have found to be useful as hypnotics for intravenous anaesthesia,are:

[0024] 2R-[4-(hexahydro-1-oxazepinyl)]-3-methoxypropionic acid,2,6-dimethoxyphenyl ester; and

[0025] 2R-[4-(hexahydro-1-oxazepinyl)]-4-methoxybutyric acid,2,6-dimethoxyphenyl ester

[0026] γ-Aminobutyric acid (GABA) is the major inhibitoryneurotransmitter within the central nervous system and it is probablethat compounds potentiating the is effects of GABA at GABA_(A) receptorswill induce anaesthesia (S. A. Zimmerman, M. V. Jones and N. L.Harrison, J. Pharmacol. Exp. Therap. 1994, 270, 987-991; N. P. Franksand W. R. Lieb, Nature 1994, 367, 607-614). Indeed there is compellingevidence that many hypnotics exert their biological activity viamodulation of GABA_(A) receptors, including steroids, barbiturates,benzodiazepines and propofol (D. L. Tanelian, P. Kosek, I. Mody and M.B. Maclver, Anesthesiology 1993, 78, 757-776). The compounds of thepresent invention have been shown to modulate the specific binding of[³⁵S]-tertbutylbicyclophosphorothionate to rat whole brain membranes,consistent with allosteric modulation of GABA_(A) receptors.

[0027] In addition to their general anaesthetic activity, the compoundsof the invention can be used as sedative and analgesic drugs and in thetreatment of GABA related diseases, such as anxiety, stress, sleepdisorders, post natal depression, and premenstrual tension, and in thealleviation of seizure.

[0028] The invention also relates to pharmaceutical compositionscomprising an alanine 2,6-dialkoxyphenyl ester derivative having thegeneral formula I or a pharmaceutically acceptable salt thereof.

[0029] The compounds of the invention may be prepared by condensation ofan appropriately R₅,R₆,R₇-substituted phenol, wherein R₅, R₆ and R₇ havethe previously given meanings, with an activated acid derivativeaccording to formula II

[0030] wherein R₁ and R₂ have the meanings as previously defined, Halmeans halogen, and is selected from iodo, bromo or chloro, preferablybromo, and X is also halogen, preferably chloride, after which theresulting intermediate ester derivative of formula III

[0031] is reacted with an amine according to the formula R₃R₄NH, whereinR₃ and R₄ have the meanings as previously defined, optionally followedby conversion into a pharmaceutically acceptable salt.

[0032] The acid halogenide according to formula II, wherein X ishalogen, can be prepared from the acid derivative according to formulaII, wherein X is OH, by treatment with an inorganic acid halide, such asthionyl chloride, or an organic acid halide, such as oxalyl chloride.The intermediate acid derivative of Formula II, wherein X is OH, can beprepared using methods well known to the skilled person, for example bytreatment of the corresponding α-amino acid, NH₂—CH(CHR₁R₂)—COOH withsodium nitrite in aqueous hydrobromic acid.

[0033] Alternatively the intermediate ester derivative of formula IIImay be prepared by condensation of an appropriately R₅,R₆,R₇-substitutedphenol, wherein R₅, R₆ and R₇ have the previously given meanings, withan acid according to Formula II, wherein X is OH, and Hal is iodo, bromoor chloro, preferably bromo, with the aid of a condensing agent, such asbromo-trispyrrolidino-phosphonium hexafluorophosphate (PyBrop),dicyclohexylcarbodiimide/N-hydroxybenzotriazole and the like.

[0034] The compounds of the invention may also be prepared bycondensation of an appropriately R₅,R₆,R₇-substituted phenol, whereinR₅, R₆ and R₇ have the previously given meanings, with an α-amino acidderivative according to the formula R₃R₄N—CH(CHR₁R₂)—CO₂H, wherein R₁R₄have the previously given meanings, with the use of a condensationagent, such as those mentioned above.

[0035] The alanine 2,6-dialkoxyphenyl ester derivatives of Formula Icontain at least one chiral carbon atom, i.e. the α-carbon atom. Thecompounds can therefore be obtained as pure stereoisomers, or as amixture of stereoisomers. Methods for asymmetric synthesis whereby thepure stereoisomers are obtained are well known in the art, e.g.synthesis with chiral induction, enantioselective enzymatic esterhydrolysis, separation of stereoisomers or enantiomers usingchromatography on chiral media. Such methods are for example describedin Chirality in Industry (edited by A. N. Collins, G. N. Sheldrake andJ. Crosby, 1992; John Wiley).

[0036] Pharmaceutically acceptable salts may be obtained by treating thefree base of the compounds according to formula I with a mineral acidsuch as hydrochloric acid, hydrobromic acid, phosphoric acid, andsulphuric acid, or with an organic acid such as for example ascorbicacid, citric acid, tartaric acid, lactic acid, maleic acid, malonicacid, fumaric acid, glycolic acid, succinic acid, propionic acid, aceticacid, methanesulphonic acid and the like.

[0037] The present invention further provides pharmaceuticalcompositions comprising an alanine 2,6-dialkoxyphenyl ester derivativehaving the general formula I, or a pharmaceutically acceptable saltthereof, in admixture with pharmaceutically acceptable auxiliaries, andoptionally other therapeutic agents. The term “acceptable” means beingcompatible with the other ingredients of the composition and notdeleterious to the recipients thereof. Compositions include e.g. thosesuitable for oral, sublingual, subcutaneous, intravenous, intramuscular,local, or rectal administration, and the like, all in unit dosage formsfor administration. The intravenous route of administration is thepreferred one when the hypnotic properties of the compounds of theinvention are to be utilized for general anaesthesia.

[0038] For oral administration, the active ingredient may be presentedas discrete units, such as tablets, capsules, powders, granulates,solutions, suspensions, and the like.

[0039] For parenteral administration, the pharmaceutical composition ofthe invention may be presented in unit-dose or multi-dose containers,e.g. injection liquids in predetermined amounts, for example in sealedvials and ampoules, and may also be stored in a freeze dried(lyophilized) condition requiring only the addition of sterile liquidcarrier, e.g. water, prior to use.

[0040] Mixed with such pharmaceutically acceptable auxiliaries, e.g. asdescribed in the standard reference, Gennaro et al., Remington'sPharmaceutical Sciences, (18th ed., Mack Publishing Company, 1990, seeespecially Part 8: Pharmaceutical Preparations and Their Manufacture),the active agent may be compressed into solid dosage units, such aspills, tablets, or be processed into capsules or suppositories. By meansof pharmaceutically acceptable liquids the active agent can be appliedas a fluid composition, e.g. as an injection preparation, in the form ofa solution, suspension, emulsion, or as a spray, e.g. a nasal spray.

[0041] For making solid dosage units, the use of conventional additivessuch as fillers, colorants, polymeric binders and the like iscontemplated. In general any pharmaceutically acceptable additive whichdoes not interfere with the function of the active compounds can beused. Suitable carriers with which the active agent of the invention canbe administered as solid compositions include lactose, starch, cellulosederivatives and the like, or mixtures thereof, used in suitable amounts.For parenteral administration, aqueous suspensions, isotonic salinesolutions and sterile injectable solutions may be used, containingpharmaceutically acceptable dispersing agents and/or wetting agents,such as propylene glycol or butylene glycol.

[0042] The invention further includes a pharmaceutical composition, ashereinbefore described, in combination with packaging material suitablefor said composition, said packaging material including instructions forthe use of the composition for the use as hereinbefore described.

[0043] The compounds of the invention may be administered for humans ina dosage of 0.001-50 mg per kg body weight, preferably in a dosage of0.1-20 mg per kg body weight.

[0044] The invention is illustrated by the following examples.

EXAMPLES

[0045] General.

[0046] Analysis of Compounds: The mass spectra of compounds of Formula Iand their salts by electron spray ionisation (ESI) afford a parent ionthat corresponds to the mass of the free base. While either the compoundof Formula I or its salt may have been analysed by this method, theresult is indicated below for the compound (and not the salt) in thefollowing examples.

Example 1

[0047] 1a: 2-Bromoacrylic acid, 2,6-dimethoxyphenyl ester.

[0048] 2,3-Dibromopropionyl chloride (30 g, 0.12 mol) and2,6-dimethoxyphenol (18 g, 0.12 mol) were dissolved in anhydrousdichloromethane (800 ml) with stirring and cooling. Triethylamine (42ml, 0.3 mol) was added dropwise over 1 h and the reaction mixture wasleft to stir for a further 3 h at room temperature. The solvent wasremoved under reduced pressure and diethyl ether (400 ml) added. Theprecipitate was then removed by filtration and the filtrate washed withwater, dried over sodium sulphate, filtered and concentrated underreduced pressure to give the title compound (28 g, 81%) as a creampowder.

[0049]¹H NMR (CDCl₃): δ3.81 (s, 6H), 6.45 (s, 1H), 6.61 (d, 2H), 7.14(t, 1H), 7.20 (s, 1H).

[0050] The following compound was prepared in a similar manner:

[0051] 1b: 2-Bromoacrylic acid, 2,6-dimethoxy-4-methylphenyl ester.

[0052]¹H NMR (CDCl₃): δ2.34 (s, 3H), 3.79 (s, 6H), 6.39-6.44 (m, 3H),7.19 (s, 1H).

Example 2

[0053] 2a: 2-Bromo-3-methoxypropionic acid, 2,6-dimethoxyphenyl ester.

[0054] 2-Bromoacrylic acid, 2,6-dimethoxyphenyl ester (12 g, 42 mmol)was dissolved in methanol (300 ml, HPLC grade) and sodium methoxide(0.23 g, 4.2 mmol) added with stirring. The resultant solution was thenstirred at room temperature for 30 minutes prior to the addition ofammonium chloride (0.5 g). The solvent was then removed under reducedpressure and diethyl ether (200 ml) added. The precipitate was removedby filtration and the filtrate evaporated under reduced pressure to givea yellow oil. Chromatography of this oil on silica using toluene as theeluent afforded the title compound (6.3 g, 48%) as a clear oil.

[0055]¹H NMR (CDCl₃): δ3.48 (s, 3H), 3.82 (s, 6H), 3.85-3.94 (m, 1H),4.01-4.09 (m, 1H), 4.66 (t, 1H), 6.60 (d, 2H), 7.17 (t, 1H).

[0056] The following compound was prepared in a similar manner:

[0057] 2b: 2-Bromo-3-methoxypropionic acid, 2,6-dimethoxy-4-methylphenylester.

[0058]¹H NMR (CDCl₃): δ2.33 (s, 3H), 3.47 (s, 3H), 3.79 (s, 6H),3.82-3.91 (m, 1H), 4.00-4.08 (m, 1H), 4.63 (t, 1H), 6.41 (s, 2H).

[0059] Utilisation of sodium ethoxide and ethanol instead of sodiummethoxide and methanol in the protocol described above afforded:

[0060] 2c: 2-Bromo-3-ethoxypropionic acid, 2,6-dimethoxyphenyl ester.

[0061]¹H NMR (CDCl₃): δ1.24 (t, 3H), 3.64 (q, 2H), 3.82 (s, 6H),3.85-3.94 (m, 1H), 4.05-4.13 (m, 1H), 4.62 (t, 1H), 6.58 (d, 2H), 7.14(t, 1H).

Example 3

[0062] 3a: 2-[4-(Hexahydro-1-oxazepinyl)]-3-methoxypropionic acid,2,6-dimethoxyphenyl ester.

[0063] 2-Bromo-3-methoxypropionic acid, 2,6-dimethoxyphenyl ester (2.6g, 8.2 mmol) was dissolved in toluene (30 ml) with stirring.Triethylamine (2.5 ml, 18.2 mmol) and hexahydro-1,4-oxazepine (1 g, 9.9mmol) were then added and the reaction mixture heated at 100° C. undernitrogen overnight. The reaction mixture was then cooled to roomtemperature and diluted with diethyl ether (100 ml). The precipitate wasremoved by filtration and washed with diethyl ether (100 ml). Thecombined organic fractions were then extracted with 1N HCl (100 ml). Theaqueous phase was subsequently basified to pH14 with 4M NaOH andextracted with diethyl ether (100 ml×2). The combined organic fractionswere dried over sodium sulphate, filtered and concentrated under reducedpressure to give a yellow oil. Chromatography of this oil on basicalumina using toluene/ethyl acetate gradient as the eluent afforded thetitle compound (0.7 g, 26%) as a clear oil which crystallised onstanding. Positive Ion ESI (M+H)⁺ 339.9

[0064] The following compounds were prepared in a similar manner:

[0065] 3b: 2-[N-Bis(2-methoxyethyl)amino]-3-methoxypropionic acid,2,6-dimethoxyphenyl ester: Positive Ion ESI (M+H)⁺ 372.2

[0066] 3c: 3-Methoxy-2-[N-thiomorpholinyl]propionic acid, 2,6-dimethoxyphenyl ester: Positive Ion ESI (M+H)⁺ 342.2

[0067] 3d: 2-[N-(Hexahydroazepinyl)]-3-methoxypropionic acid,2,6-dimethoxyphenyl ester: Positive Ion ESI (M+H)⁺ 337.8

[0068] 3e: 3-Methoxy-2-[4-morpholinyl]propionic acid,2,6-dimethoxyphenyl ester. Positive Ion ESI (M+H)⁺ 326.0

[0069] 3f: 2-[N-Bis(3-methoxypropyl)amino]-3-methoxypropionic acid,2,6-dimethoxyphenyl ester: Positive Ion ESI (M+H)⁺ 399.9

[0070] 3g: 2-[N-Bis(3-ethoxyethyl)amino]-3-methoxypropionic acid,2,6-dimethoxyphenyl ester: Positive Ion ESI (M+H)⁺ 400.2

[0071] 3h: 3-Methoxy 2-[1-pyrollidinyl]propionic acid,2,6-dimethoxyphenyl ester. Positive Ion ESI (M+H)⁺ 310.2

[0072] 3i: 2-[N-Bis(2-methoxyethyl)amino]-3-methoxypropionic acid,2,6-dimethoxy-4-methylphenyl ester: Positive Ion ESI (M+H)⁺ 386.2

[0073] 3j: 3-Methoxy-2-[N-thiomorpholinyl]propionic acid,2,6-dimethoxy-4-methylphenyl ester: Positive Ion ESI (M+H)⁺ 356.2

[0074] 3k: 3-Methoxy-2-[4-morpholinyl]propionic acid,2,6-dimethoxy-4-methylphenyl ester: Positive Ion ESI (M+H)⁺ 340.2

[0075] 3l: 3-Methoxy-2-[N-(2-Methoxyethyl)methylamino]propionic acid,2,6-dimethoxy-4-methylphenyl ester: Positive Ion ESI (M+H)⁺ 342.2

[0076] 3m: 2-[4-(Hexahydro-1-oxazepinyl)]-3-methoxypropionic acid,2,6-dimethoxy-4-methylphenyl ester: Positive Ion ESI (M+H)⁺ 354.0

[0077] 3n: 3-Methoxy-2-[1-pyrrolidinyl]propionic acid,2,6-dimethoxy-4-methylphenyl ester: Positive Ion ESI (M+H)⁺ 324.0

[0078] 3o: 3-Methoxy-2-[1-piperidinyl]propionicacid,2,6-dimethoxy-4-methylphenyl ester: Positive Ion ESI (M+H)⁺ 338.2

[0079] 3p: 2-[N-Bis(3-methoxypropyl)amino]-3-methoxypropionic acid,2,6-dimethoxy-4-methylphenyl ester: Positive Ion ESI (M+H)⁺ 414.4

[0080] 3q: 2-[N-Bis(2-ethoxyethyl)amino]-3-methoxypropionic acid,2,6-dimethoxy-4-methylphenyl ester: Positive Ion ESI (M+H)⁺ 414.0

[0081] 3r: 3-Ethoxy-2-[4-(Hexahydro-1-oxazepinyl)]propionic acid,2,6-dimethoxyphenyl ester: Positive Ion ESI (M+H)⁺ 353.7

Example 4

[0082] 4a: 2-[N-Bis(2-methoxyethyl)amino]-3-methoxypropionic acid,2,6-dimethoxy-4-methylphenyl ester.

[0083] Sodium ethoxide (0.2 g, 3 mmol) was added to a solution of2-bromo-3-methoxypropionic acid, 2,6-dimethoxy-4-methylphenyl ester (8g, 26.3 mmol) in ethanol (200 ml) and stirred at room temperature for 30minutes. Ammonium chloride (0.32 g, 6 mmol) was then added and thesolvent removed under reduced pressure. After removal of insolublematerial by filtration, the solvent was removed under reduced pressureto give a clear oil. This oil was committed to further reaction withoutfurther purification. Bis-(2-methoxyethyl)amine (4.1 ml, 28 mmol) andtriethylamine (4 ml, 28 mmol) were added to a solution of the productjust described (4.8 g, 13.9 mmol) in toluene (10 ml) and stirred atreflux for 5 h. After cooling to room temperature, diethyl ether wasadded and the insoluble material removed by filtration. The organicfraction was then washed with water and extracted with dilutehydrochloric acid. The aqueous acidic fraction was subsequently basifiedwith dilute sodium hydroxide to pH14 and extracted with diethyl ether(×2). The combined extracts were dried over sodium sulphate, filteredand the solvent removed under reduced pressure to give a yellow oil.Chromatography of this oil on alumina afforded the title compound (0.75g).

[0084] Positive Ion ESI (M+H)⁺ 400.4

Example 5

[0085] 5a: Propanedioic, (2-methoxyethyl)-, diethyl ester.

[0086] Sodium (8.4 g, 0.36 mol) was added portionwise with stirring toethanol (400 ml) over 30 minutes. Once evolution of hydrogen had ceased,diethyl malonate (54.6 ml, 0.36 mol) was added slowly and the solutionstirred for a further 30 minutes. 2-Bromoethyl methyl ether (50 g, 0.36mol) was then added and the resultant solution heated at reflux withstirring under nitrogen for 4 h. A precipitate was evident after 1.5 h.The suspension was then allowed to cool to room temperature overnightand the precipitate removed by filtration. The solvent was removed underreduced pressure and the crude product dissolved in diethyl ether (200ml) and washed with water (200 ml). The organic phase was then driedover sodium sulphate, filtered and concentrated under reduced pressureto give a yellow oil. The crude product was then purified by vacuumdistillation (bp 84-86° C., 0.5 mmHg) to give the title compound (50 g,64%) as a clear oil.

[0087]¹H NMR (CDCl₃): δ1.27 (t, 6H), 2.16 (q, 2H), 3.31 (s, 3H), 3.41(t, 2H), 3.52 (t, 1H), 4.20 (q, 4H).

[0088] The following compound was prepared in a similar manner:

[0089] 5b: Propanedioic, (2-ethoxyethyl)-, diethyl ester.

[0090]¹H NMR (CDCl₃): δ1.17 (t, 3H), 1.27 (t, 6H), 2.18 (q, 2H),3.40-3.50 (m, 4H), 3.55 (t, 1H), 4.11-4.28 (m, 4H).

Example 6

[0091] 6a: Propanedioic acid, (2-methoxyethyl)-.

[0092] Potassium hydroxide (61 g, 0.92 mol) was dissolved in 95/5ethanol/water (400 ml) with stirring under nitrogen. Propanedioic,2-methoxyethyl)-, diethyl ester (50 g, 0.23 mol) was then added and theresultant solution stirred at reflux overnight. The solution was thenallowed to cool to room temperature and the solvent removed underreduced pressure. The residue was dissolved in a minimal amount of icedwater and acidified to pH1 with 5N HCl. This solution was extracted withdiethyl ether (250 ml ×3) and the combined ether fractions were driedover sodium sulphate, filtered and concentrated under reduced pressureto give the title compound (28.7 g, 77%) as a clear oil.

[0093] hu 1H NMR (CDCl₃): δ1.21 (t, 1H), 2.19-2.29 (m, 1H), 3.35 (s,3H), 3.47-3.56 (m, 2H), 3.61 (t, 1H).

[0094] The following compound was prepared in a similar manner:

[0095] 6b: Propanedioic acid, (2-ethoxyethyl)-.

[0096]¹H NMR (CDCl₃): δ1.10-1.31 (m, 4H), 2.18-2.26 (m, 1H), 3.39-3.64(m, 4H), 3.66-3.79 (m, 1H).

Example 7

[0097] 7a: 2-Bromo-4-methoxybutyric acid.

[0098] Propanedioic acid, (2-methoxyethyl)-(28.7 g, 0.18 mol) wasdissolved in diethyl ether (300 ml) and three drops of 47% aqueoushydrobromic acid were added with stirring. Bromine (9.2 ml, 0.18 mol)was then added dropwise over minutes and the solution stirred at roomtemperature for a further 30 minutes. The solution was washed withdilute aqueous sodium metabisulphite, dried over sodium sulphate,filtered and concentrated under reduced pressure to give an orange oil(42 g). This oil was heated to 150° C. at atmospheric pressure for 30minutes to effect decarboxylation. After cooling to 50° C., vacuumdistillation (bp 104-106° C., 0.5 mmHg) afforded the title compound(19.2 g, 55%) as a clear viscous oil.

[0099]¹H NMR (CDCl₃): δ2.14-2.24 (m, 1H), 2.32-2.45 (m, 1H), 3.36 (s,3H), 3.52-3.61 (m, 2H), 4.46-4.52 (m, 1H).

[0100] The following compound was prepared in a similar manner:

[0101] 7b: 2-Bromo-4-ethoxybutyric acid.

[0102]¹H NMR (CDCl₃): δ1.19 (t, 3H), 2.12-2.27 (m, 1H), 2.32-2.42 (m,1H), 3.44-3.55 (m, 2H), 3.56-3.64 (m, 2H), 4.45-4.53 (m, 1H).

Example 8

[0103] 8a: 2-Bromo-4-methoxybutyryl chloride.

[0104] 2-Bromo-4-methoxybutyric acid (19.2 g, 98 mmol) was dissolved inanhydrous dichloromethane and oxalyl chloride (10.2 ml, 117 mmol) addedwith stirring. One drop of pyridine was then added and the resultantsolution stirred at room temperature overnight. The solvent and excessoxalyl chloride were removed under reduced pressure to give the titlecompound (20.4 g, 9 %) as a clear oil. This oil was used in subsequentreactions without further purification.

[0105]¹H NMR (CDCl₃): δ2.16-2.30 (m, 1H), 2.40-2.52 (m, 1H), 3.35 (s,3H), 3.51-3.60 (m, 2H), 4.70-4.80 (m, 1H).

[0106] The following compound was prepared in a similar manner:

[0107] 8b: 2-Bromo4-ethoxybutyryl chloride.

[0108]¹H NMR (CDCl₃): δ1.19 (t, 3H), 2.19-2.29 (m, 1H), 2.41-2.52 (m,1H), 3.41-3.52 (m, 2H), 3.53-3.64 (m, 2H), 3.71-3.80 (m, 1H).

Example 9

[0109] 9a: 2-Bromo-4-methoxybutyric acid, 2,6-dimethoxyphenyl ester.

[0110] 2-Bromo-4-methoxybutyryl chloride (10.7 g, 50 mmol) was dissolvedin anhydrous dichloromethane and 2,6-dimethoxyphenol (8.4 g, 54 mmol)added. The resultant solution was then cooled using an ice bath andtriethylamine (8.3 ml, 59 mmol) added dropwise over 30 minutes. Theexternal cooling bath was then removed and the reaction mixture stirredat room temperature for a further 30 minutes. The solvent was removedunder reduced pressure and diethyl ether (200 ml) added. The precipitatewas removed by filtration and the filtrate washed with water (100 ml),dried over sodium sulphate, filtered and concentrated under reducedpressure, to give the title compound (15.2 g, 9 %) as a viscous yellowoil.

[0111]¹H NMR (CDCl₃): δ2.26-2.37 (m, 1H), 2.48-2.59 (m, 1H), 3.38 (s,3H), 3.57-3.66 (m, 2H), 3.81 (s, 6H), 4.71-4.80 (m, 1H), 6.60 (d, 2H),7.12 (t, 1H).

[0112] The following compounds were prepared in a similar manner:

[0113] 9b: 2-Bromo-4-methoxybutyric acid, 2,6-dimethoxy-4-methylphenylester.

[0114]¹H NMR (CDCl₃): δ2.26-2.36 (m, 4H), 2.48-2.59 (m, 1H), 3.37 (s,3H), 3.55-3.63 (m, 2H), 3.78 (s, 6H), 4.69-4.78 (m, 1H), 6.40 (s, 2H).

[0115] 9c: 2-Bromo-4-ethoxybutyric acid, 2,6-dimethoxyphenyl ester.

[0116]¹H NMR (CDCl₃): δ1.21 (t, 3H), 2.26-2.37 (m, 1H), 2.47-2.59 (m,1H), 3.51 (q, 2H), 3.61-3.69 (m, 2H), 3.80 (s, 6H), 4.71-4.80 (m, 1H),6.62 (d, 2H), 7.13 (t, 1H).

[0117] 9d: 2-Bromo-4-ethoxybutyric acid, 2,6-dimethoxy-4-methylphenylester.

[0118]¹H NMR (CDCl₃): δ1.21 (t, 3H), 2.26-2.36 (m, 4H), 2.46-2.59 (m,1H), 3.51 (q, 2H), 3.60-3.69 (m, 2H), 3.79 (s, 6H), 4.70-4.80 (m, 1H),6.41 (s, 2H).

Example 10

[0119] 10a: 2-[4-(Hexahydro-1-oxazepinyl)]-4-methoxybutyric acid,2,6-dimethoxyphenyl ester.

[0120] 2-Bromo-4-methoxybutyric acid, 2,6-dimethoxyphenyl ester (4.4 g,13.3 mmol) was dissolved in toluene (30 ml). To this stirred solutionwas added triethylamine (4.6 ml, 33.3 mmol) and hexahydrooxazepinehydrochloride (1:1) salt (2.3 g, 16.7 mmol), and the reaction heated at100° C. under nitrogen overnight. The reaction mixture was allowed tocool to room temperature and diluted. with diethyl ether (100 ml). Theprecipitate was removed by filtration and washed with diethyl ether (100ml). The combined organic fractions were then extracted with 1N HCl (200ml). The aqueous phase was subsequently basified to pH14 with 4M NaOHand extracted with diethyl ether (200 ml×2). The combined organicfractions were dried over sodium sulphate, filtered and concentratedunder reduced pressure to give a yellow oil. Chromatography of this oilon basic alumina using toluene/ethyl acetate gradient as the eluentafforded the title compound (3.1 g, 64%) as a clear viscous oil.

[0121]¹H NMR (CDCl₃): δ1.81-2.08 (m, 4H), 2.12-2.24 (m, 1H), 2.88-2.99(m, 2H), 3.07-3.19 (m, 2H), 3.38 (s, 3H), 3.51-3.88 (m, 14H), 6.60 (d,2H), 7.12 (t, 1H). Positive Ion ESI (M+H)⁺ 353.8

[0122] The following compounds were prepared in a similar manner:

[0123] 10b: 4-Methoxy-2-[4-morpholinyl]butyric acid, 2,6-dimethoxyphenylester.

[0124] Positive Ion ESI (M+H)⁺ 339.8

[0125] 10c: 4-Methoxy-2-[1-(1,2,3,6-tetrahydropyridinyl)]butyric acid,2,6-dimethoxyphenyl ester: Positive Ion ESI (M+H)⁺ 336.0

[0126] 10d: 4-Methoxy-2-[1-(4-methoxypiperidinyl)]butyric acid,2,6-dimethoxyphenyl ester: Positive Ion ESI (M+H)⁺ 367.5

[0127] 10e: 2-[l-(Hexahydroazepinyl)]-4-methoxybutyric acid,2,6-dimethoxyphenyl ester: Positive Ion ESI (M+H)⁺ 367.9

[0128] 10f: 4-Methoxy-2-[1-piperidinyl]butyric acid, 2,6-dimethoxyphenylester.

[0129] Positive Ion ESI (M+H)⁺ 337.6

[0130] 10g: 2-[N-(Bis(2-ethoxyethyl)amino)]-4-methoxybutyric acid,2,6-dimethoxyphenyl ester: Positive Ion ESI (M+H)⁺ 414.1

[0131] 10h: 2-[N-(Bis(2-methoxyethyl)amino)]-4-methoxybutyric acid,2,6-dimethoxyphenyl ester.

[0132]¹H NMR (CDCl₃): δ1.92-2.03 (m, 1H), 2.15-2.24 (m, 1H), 2.97-3.03(m, 4H), 3.35 (s, 6H), 3.37 (s, 3H), 3.45-3.51 (m, 4H), 3.55-3.70 (m,2H), 3.79 (s, 6H), 3.84-3.91 (m, 1H), 6.60 (d, 2H), 7.12 (t, 1H).

[0133] Positive Ion ESI (M+H)⁺ 386.0

[0134] 10i: 4-Methoxy-2-[4-morpholinyl]butyric acid,2,6-dimethoxy-4-methylphenyl ester: Positive Ion ESI (M+H)⁺ 354.0

[0135] 10j: 2-[4-(Hexahydro-1-oxazepinyl)]-4-methoxybutyric acid,2,6-dimethoxy-4-methylphenyl ester: Positive Ion ESI (M+H)⁺ 368.0

[0136] 10k: 4-Methoxy-2-[1-(4-methoxypiperidinyl)]butyric acid,2,6-dimethoxy4-methylphenyl ester: Positive Ion ESI (M+H)⁺ 382.0

[0137] 10l: 2-[N-(Bis(2-methoxyethyl)amino)]-4-methoxybutyric acid, 2,6-dimethoxy-4-methylphenyl ester.

[0138]¹H NMR (CDCl₃): δ1.89-2.00 (m, 1H), 2.11-2.22 (m, 1H), 2.32 (s,3H), 2.93-3.02 (m, 4H), 3.35 (s, 6H), 3.37 (s, 3H), 3.43-3.50 (m, 4H),3.51-3.68 (m, 2H), 3.77 (s, 6H), 3.81-3.90 (m, 1H), 6.40 (s, 2H).

[0139] Positive Ion ESI (M+H)⁺ 400.1

[0140] 10m: 2-[N-(Bis(2-ethoxyethyl)amino)]-4-methoxybutyric acid,2,6-dimethoxy-4-methylphenyl ester.

[0141]¹H NMR (CDCl₃): δ1.19 (t, 6H), 1.91-2.01 (m, 1H), 2.12-2.23 (m,1H), 2.32 (s, 3H), 2.98 (t, 4H), 3.36 (s, 3H), 3.48-3.70 (m, 10H), 3.76(s, 6H), 3.82-3.89 (m, 1H), 6.40 (s, 2H).

[0142] Positive Ion ESI (M+H)⁺ 428.3

[0143] 10n: 2-[1-(Hexahydroazepinyl)]-4-methoxybutyric acid,2,6-dimethoxy-4-methylphenyl ester: Positive Ion ESI (M+H)⁺ 365.9

[0144] 10o: 4-Ethoxy-2-[4-morpholinyl]butyric acid, 2,6-dimethoxyphenylester.

[0145] Positive Ion ESI (M+H)⁺ 354.0

[0146] 10p 4-Ethoxy-2-[4-(hexahydro-1-oxazepinyl)]butyric acid,2,6-dimethoxyphenyl ester: Positive Ion ESI (M+H)⁺ 367.8

[0147] 10q: 4-Ethoxy-2-[1-hexahydroazepinyl]butyric acid,2,6-dimethoxyphenyl ester: Positive Ion ESI (M+H)⁺ 366.0

[0148] 10r: 2-[N-(Bis(2-methoxyethyl)amino)]-4-ethoxybutyric acid,2,6-dimethoxyphenyl ester.

[0149]¹H NMR (CDCl₃): δ1.22 (t, 3H), 1.90-2.01 (m, 1H), 2.12-2.23 (m,1H), 2.98 (t, 4H), 3.35 (s, 6H), 3.41-3.69 (m, 8H), 3.79 (s, 6H), 3.86(dd, 1H), 6.60 (d, 2H), 7.10 (t, 1H).

[0150] Positive Ion ESI (M+H)⁺ 399.8

[0151] 10s: 2-[N-(Bis(2-ethoxyethyl)amino)]-4-ethoxybutyric acid,2,6-dimethoxyphenyl ester.

[0152]¹H NMR (CDCl₃): δ1.13-1.25 (m, 9H), 1.90-2.02 (m, 1H), 2.11-2.23(m, 1H), 2.93-3.02 (m, 4H), 3.46-3.56 (m, 10H), 3.57-3.71 (m, 2H), 3.79(s, 6H), 3.89 (t, 1H), 6.59 (d, 2H), 7.10 (t, 1H).

[0153] Positive Ion ESI (M+H)⁺ 428.2

[0154] 10t: 4-Ethoxy-2-[4-morpholinyl]butyric acid,2,6-dimethoxy-4-methylphenyl ester: Positive Ion ESI (M+H)⁺ 367.8

[0155] 10u: 4-Ethoxy-2-[1-hexahydroazepinyl]butyric acid,2,6-dimethoxy-4-methylphenyl ester: Positive Ion ESI (M+H)⁺ 380.2

[0156] 10v: 2-[N-(Bis(2-methoxyethyl)amino)]-4-ethoxybutyric acid,2,6-dimethoxy-4-methylphenyl ester.

[0157]¹H NMR (CDCl₃): δ1.22 (t, 3H), 1.87-1.99 (m, 1H), 2.10-2.22 (m,1H), 2.32 (s, 3H), 2.98 (t, 4H), 3.35 (s, 6H), 3.41-3.69 (m, 8H), 3.76(s, 6H), 3.84 (dd, 1H), 6.40 (s, 2H).

[0158] Positive Ion ESI (M+H)⁺ 413.8

[0159] 10w: 4-Ethoxy-2-[4-(hexahydro-1-oxazepinyl)]butyric acid,2,6-dimethoxy-4-methylphenyl ester: Positive Ion ESI (M+H)⁺ 382.2

Example 11

[0160] N-tert-Butoxycarbonyl-threonine, triethylamine salt.

[0161] Threonine (90 g, 0.76 mol) and triethylamine (157 ml, 1.13 mol)were dissolved in aqueous dioxan (1000 ml, 50:50 vol:vol) with stirringand 2-(tert-butoxycarbonyloxyimino)-2-phenylacetonitrile (204 g, 1.0mol) was added. The reaction mixture was stirred at room temperature for18 hours. The solvent was removed under reduced pressure to give aviscous yellow oil. The oil was dissolved in diethyl ether (500 ml),extracted with water (4×100 ml), and the aqueous extracts were combinedand washed with diethyl ether (100 ml). The aqueous phase wasconcentrated under reduced pressure to give the title compound (214 g,88%) as a viscous yellow oil.

[0162]¹H NMR (D₂O): δ1.30 (d, 3H), 1.39 (t, 9H), 1.55 (s, 9H), 3.30 (q,6H), 3.98-4.02 (m, 1H), 4.27-4.36 (m, 1H).

Example 12

[0163] N-tert-Butoxycarbonyl-threonine, sodium salt.

[0164] The triethylamine salt of N-tert-butoxycarbonyl-threonine (210 g,066 mol) was dissolved in methanol (1500 ml) and sodium hydroxidepellets (26.4 g, 0.66 mol) were added with ice cooling. After 10 minutesthe ice bath was removed and the reaction was stirred at roomtemperature until all the sodium hydroxide had dissolved. The solventwas then removed under reduced pressure to give a colourless gum whichwas triturated with ethyl acetate (400 ml) to give the title compound(164 g, quantitative yield) as a white solid.

[0165]¹H NMR (D₂O): δ1.20 (d, 3H), 1.44 (s, 9H), 3.80-3.87 (m, 1H),4.11-4.22 (m, 1H).

Example 13

[0166] N-tert-Butoxycarbonyl-O-methyl-threonine.

[0167] 2-Propanol (60 ml, 0.78 mol) was dissolved in anhydroustetrahydrofuran (150 ml) and sodium hydride (26.6 g, 0.665 mol, 60%dispersion in oil) was added portion wise at room temperature under anitrogen atmosphere with stirring. The reaction mixture was cooled to 0°C. and the sodium salt of N-tert-butoxycarbonyl-threonine (40 g, 0.165mol) was added portionwise followed by anhydrous tetrahydrofuran (450ml) and stirred for 1.5 h. lodomethane (69 ml, 1.1 mol) was dissolved inanhydrous tetrahydrofuran (500 ml) and added dropwise to the reactionmixture at such a rate as to maintain the temperature between 0° C. and5° C. The reaction mixture was stirred at room temperature for 72 h thenallowed to stand for 48 h. The solvent was removed under reducedpressure and the residue was dissolved in water (200 ml) and ethylacetate (100 ml). The organic layer was removed and the aqueous phasewas extracted with ethyl acetate (2×100 ml). The pH of the aqueous phasewas adjusted to pH 4 with 2N HCl and extracted with ethyl acetate (3×100ml). The organic extracts were combined and washed with water (100 ml),saturated sodium thiosulphate solution (100 ml) and finally saturatedsodium chloride solution (100 ml). The organic solution was dried oversodium sulphate, filtered and evaporated under reduced pressure to givethe title compound (4.69 g, 13%) as a pale yellow solid.

[0168]¹H NMR (CDCl₃): δ1.21 (d, 3H), 1.47 (s, 9H), 3.39 (s, 3H),3.94-4.03 (m, 1H), 4.34 (dd, 1H), 5.30 (d, 1H).

Example 14

[0169]2-Bromo-3-methoxybutanoic acid.

[0170] N-tert-Butoxycarbonyl-threonine (2 g, 8.6 mmol) was stirred inwater (12 ml) and hydrobromic acid (7.96 ml, 68.8 mmol) and cooled to 0°C. Sodium nitrite was dissolved in water (10 ml) and added dropwise tothe cooled reaction mixture. The reaction was stirred at roomtemperature for 18 h. The reaction mixture was poured into water (100ml), extracted with diethyl ether (3×50 ml), and the organic extractswere combined and washed with saturated sodium metabisulphite solution(50 ml) followed by saturated sodium chloride. solution (50 ml). Thediethyl ether was removed under reduced pressure to give the titlecompound (0.865 g, 50%) as a yellow oil.

[0171]¹H NMR (CDCl₃): δ1.35 (d, 3H), 3.46 (s, 3H), 3.76-3.82 (m, 1H),4.33 (d, 1H).

Example 15

[0172] 2-Bromo-3-methoxybutyryl chloride.

[0173] 2-Bromo-3-methoxybutanoic acid (0.865 g, 4.4 mmol) was dissolvedin dichloromethane (15 ml) and cooled to 0° C. and oxalyl chloride (0.8ml, 9.2 mmol) was added dropwise followed by one drop of pyridine(catalytic). The reaction mixture was stirred at room temperature for 18h and the solvent was then removed under reduced pressure to give thetitle compound (0.944 g, 100%) as a yellow oil.

[0174]¹H NMR (CDCl₃): δ1.37 (d, 3H), 3.42 (s, 3H), 3.89-3.97 (m, 1H),4.60 (d, 1H).

Example 16

[0175]2-Bromo-3-methoxybutanoic acid, 2,6-dimethoxy-4-methylphenylester.

[0176] 2-Bromo-3-methoxybutyryl chloride (0.944 g, 4.4 mmol) wasdissolved in dichloromethane (20 ml) with 2,6-dimethoxy-4-methylphenol(0.740 g, 4.4 mmol) and cooled to 0° C. Triethylamine (0.64 ml, 4.6mmol) was added dropwise at 0° C. and stirred at room temperature for 18h. The reaction mixture was diluted with dichloromethane (100 ml),washed with water (3×50 ml) followed by saturated sodium chloridesolution (50 ml), dried over sodium sulphate, filtered and evaporatedunder reduced pressure to give the title compound (1.32 g, 86%) as ayellow oil.

[0177]¹H NMR (CDCl₃): δ1.41 (d, 3H), 2.33 (s, 3H), 3.50 (s, 3H), 3.80(s, 6H), 3.85-3.95 (m, 1H), 4.48 (d, 1H), 6.40 (s, 2H).

Example 17

[0178] 3-Methoxy-2-(4-morpholinyl)butanoic acid,2,6-dimethoxy-4-methylphenyl ester.

[0179] Morpholine (0.66 ml, 7.6 mmol), was added to2-bromo-3-methoxybutanoic acid, 2,6-dimethoxy-4-methylphenyl ester (1.32g, 3.8 mmol) and heated to 100° C. for 5 h with stirring. The reactionmixture was diluted with diethyl ether (100 ml) and filtered. Thefiltrate was washed with water (50 ml) followed by 2N HCl (2×50 ml). Theacidic extracts were combined and basified with 4N NaOH and extractedwith diethyl ether (4×50 ml). The organic extracts were combined andwashed with water (50 ml) followed by saturated sodium chloride solution(50 ml), dried over sodium sulphate, filtered and evaporated to give abrown oil, This was fractionated on Merck 7729 silica using a gradientelution from 95:5 petroleum ether:ethyl acetate to 80:20 petroleumether:ethyl acetate to give the title compound (0.273 g, 20%) as ayellow oil.

[0180] Positive Ion ESI (M+H)⁺ 353.8

Example 18

[0181] 18a: 2,3-Di-(N-thiomorpholinyl)propanoic acid,2,6-dimethoxyphenyl ester.

[0182] Thiomorpholine (1.8 ml, 19.1mmol) was added to a stirred solutionof 2-bromoacrylic acid, 2,6-dimethoxyphenyl ester (2.5 g, 8.7 mmol) andtriethylamine (3.6 ml, 26.1 mmol) in dichloromethane (3 ml). Theresultant solution was stirred at room temperature for 1.5 h prior tothe addition of diethyl ether. The precipitate was removed by filtrationand the solvent removed under reduced pressure to give the crude productas an oil. Chromatography of this oil on alumina afforded the titlecompound (1.2 g)

[0183] Positive Ion ESI (M+H)⁺ 413.5

[0184] The following compounds were prepared in a similar manner:

[0185] 18b: 2,3-Di-[4-(2,2-dimethylmorpholinyl)]propanoic acid,2,6-dimethoxyphenyl ester.

[0186] Positive Ion ESI (M+H)⁺ 437.5

[0187] 18c: 2,3-Di-(4-morpholinyl)propanoic acid, 2,6-dimethoxyphenylester.

[0188]¹H NMR (CDCl₃): δ2.50-2.59 (m, 2H), 2.59-2.70 (m, 3H), 2.70-2.78(m, 2H), 3.00-3.06 (m, 1H), 3.65-3.80 (m, 9H), 3.82 (s, 6H), 6.62 (d,2H), 7.14 (t, 1H). Positive Ion ESI (M+H)⁺ 381.1

Example 19

[0189] 19a: 3-(4-Morpholinyl)-2-(N-thiomorpholinyl)propanoic acid,2,6-dimethoxyphenyl ester.

[0190] Morpholine (5.3 ml, 60.6 mmol) was added to a solution of2-bromoacrylic acid, 2,6-dimethoxyphenyl ester (17.4 g, 60.6 mmol) indichloromethane (350 ml) and stirred at room temperature overnight. TLCanalysis after this time showed complete consumption of 2-bromoacrylicacid, 2,6-dimethoxyphenyl ester. The solution was then concentratedunder reduced pressure and carried forward without further purification.Thiomorpholine (0.45 ml) and diisopropylethylamine (2.1 ml) were addedto a portion of the above intermediate in dichloromethane and stirred atroom temperature overnight. The solvent was then removed under reducedpressure and diethyl ether added. The precipitate was removed byfiltration and the solvent removed under reduced pressure to give thecrude product as an oil. Chromatography of this oil on alumina affordedthe title compound (0.64 g).

[0191] Positive Ion ESI (M+H)⁺ 397.5

[0192] The following compounds were prepared in a similar manner:

[0193] 19b:3-(4-Morpholinyl)-2-(1,2,3,4-tetrahydroisoquinoline)propanoic acid,2,6-dimethoxyphenyl ester: Positive Ion ESI (M+H)⁺

[0194] 19c:2-[N-(2,2-Dimethylthiomorpholinyl)]-3-(4-morpholinyl)propanoic acid,2,6-dimethoxyphenyl ester: Positive Ion ESI (M+H)⁺ 425.0

[0195] 19d: 2-[(R)-4-(2-Methylmorpholinyl)]-3-(4-morpholinyl)propanoicacid, 2,6-dimethoxyphenyl ester: Positive Ion ESI (M+H)⁺ 395.5

[0196] 19e: 2-[(R)-4-(2-Ethylmorpholinyl)]-3-(4-morpholinyl)propanoicacid, 2,6-dimethoxyphenyl ester: Positive Ion ESI (M+H)⁺ 409.5

[0197] 19f:2-[4-(2-Ethyl-2-methylmorpholinyl)]-3-(4-morpholinyl)propanoic acid,2,6-dimethoxyphenyl ester: Positive Ion ESI (M+H)⁺ 423.5

[0198] 19g: 3-(4-Morpholinyl)-2-(1-piperidinyl)propanoic acid,2,6-dimethoxyphenyl ester: Positive Ion ESI (M+H)⁺ 379.0

[0199] 19h: 2-[(R)-Isopropylmorpholinyl)]-3-(4-morpholinyl)propanoicacid, 2,6-dimethoxyphenyl ester: Positive Ion ESI (M+H)⁺ 423.5

[0200] 19i: 2-(4-Morpholinyl)-3-(N-thiomorpholinyl)propanoic acid,2,6-dimethoxyphenyl ester: Positive Ion ESI (M+H)⁺ 397.0

[0201] 19j:2-(4-Morpholinyl)-3-(1,2,3,4-tetrahydroisoquinoline)propanoic acid,2,6-dimethoxyphenyl ester: Positive Ion ESI (M+H)⁺ 427.0

[0202] 19k:3-(1,2,3,6-Tetrahydropyridinyl)-2-(N-thiomorpholinyl)propanoic acid,2,6-dimethoxyphenyl ester: Positive Ion ESI (M+H)⁺ 393.5

Example 20

[0203] 20a: Propanoic acid, 2,3-di(4-morpholinyl),4-allyl-2,6-dimethoxyphenyl ester.

[0204] To a stirred solution of 4-allyl-2,6-dimethoxyphenol (3.5 g) and2,3-dibromopropionyl chloride (4,g) in dichloromethane (150 ml) wasadded triethylamine (5.6 ml) and stirring was continued for 24 h. Thesolvent was removed under reduced pressure and diethyl ether (100 ml)added. The suspension was filtered and the filtrate was concentratedunder reduced pressure. To this was added dichloromethane (10 ml),triethylamine (6.7 ml), morpholine (3.5 ml) and the reaction mixture wasstirred for 2 h.

[0205] Chromatography on alumina gave the title compound (0.4 g, 6%) asan oil.

[0206] Positive ion ESI (M+H)⁺ 421

[0207] The following compounds were prepared in a similar manner:

[0208] 20b: Propanoic acid, 2,3-di(4-morpholinyl), 2,6-diethoxyphenylester.

[0209] Positive ion ESI (M+H)⁺ 409

[0210] 20c: Prorpanoic acid, 2,3-di(4-morpholinyl),4-formyl-2,6-dimethoxyphenyl ester: Positive ion ESI (M+H)⁺ 409.5

[0211] 20d: Propanoic acid, 2,3-di(4-morpholinyl),2-allyl-6-methoxyphenyl ester.

[0212] Positive ion ESI (M+H)⁺ 391.5

Example 21

[0213] 21a: 2,4-Di-(4-morpholinyl)butanoic acid, 2,6-dimethoxyphenylester.

[0214] Triethylamine (7 ml, 60 mmol) was added to a solution oftert-butyl-2,4-dibromobutyrate (3.2 ml, 16.6 mmol) in dichloromethane(minimum). Morpholine (3.2 ml, 36 mmol) was then added and the solutionstirred at room temperature overnight. The solvent was removed underreduced pressure and ethyl acetate added. The solution was then washedwith water and saturated brine, dried over sodium sulphate, filtered andthe solvent removed under reduced pressure to give a yellow oil (3.1 g).The oil was dissolved in trifluoroacetic acid (10 ml) anddichloromethane (10 ml) and stirred at room temperature for 2.5 h. Thesolvent was removed under reduced pressure and any residualtrifluoroacetic acid was azeotroped with dry toluene to give a yellowoil. The trifluoroacetate salt was then dissolved in dichloromethane(100 ml). To this solution was added diisopropylethylamine (5.7 ml, 32.7mmol), 2,6-dimethoxyphenol (1.68 g, 10.9 mmol), PyBrOP (5.1 g, 10.9mmol) and dimethylaminopyridine (cat) and the resultant solution stirredat room temperature for 3 h. The solvent was removed under reducedpressure and ethyl acetate added to give a suspension which wasvigorously stirred for 15 minutes. Once the suspension had settled theethyl acetate was decanted off and washed with water and saturatedbrine, dried over sodium sulphate, filtered and the solvent removedunder reduced pressure to give an oil. Chromatography of this oil onalumina afforded the title compound (0.45 g).

[0215]¹H NMR (CDCl₃): δ1.90-1.99 (m, 1H), 2.06-2.16 (m, 1H), 2.40-2.61(m, 6H), 2.70-2.78 (m, 2H), 2.85-2.95 (m, 2H), 3.52-3.62 (m, 1H),3.70-3.80 (m, 8H), 3.82 (s, 6H), 6.61 (d, 2H), 7.13 (t, 1H).

[0216] Positive Ion ESI (M+H)⁺ 395.5

[0217] The following compound was prepared in a similar manner:

[0218] 21b: 2,4-Di-[(4-(2,2-dimethylmorpholinyl)]butanoic acid,2,6-dimethoxyphenyl ester: Positive Ion ESI (M+H)⁺ 451.4

Example 22

[0219]2-Butenedioic acid (2Z)-, monomethyl ester.

[0220] A solution of maleic anhydride (30 g) in methanol (200 ml) washeated to reflux for 0.5 h. The reaction mixture was allowed to cool andwas then concentrated under reduced pressure to give the title compound(39 g, 98%) as a clear oil. ¹H NMR (CDCl₃); δ3.91 (s, 3H), 6.39 (d, 1H),6.46 (d, 1H)

Example 23

[0221] Butanedioic, 2-[N-bis(2-methoxyethyl)amino]-, 4-methyl ester,sodium salt.

[0222] A mixture of 2-butenedioic acid (2Z)-, monomethyl ester (23 g)and bis(2-methoxyethyl)amine (80 ml) were heated, under nitrogen, at130° C. for 1 h. The reaction mixture was allowed to cool to roomtemperature and the excess bis(2-methoxyethyl)amine removed under highvacuum. The resulting oil was redissolved in methanol (300 ml) andsodium hydroxide (7.1 g) was added. The suspension was stirred for 2 hand then concentrated under reduced pressure to give the title compound(48 g, 95%) as a brown oil.

[0223] Positive ion ESI (M+H)⁺ 264.1

Example 24

[0224] 24a: Butanedioic, 2-[N-bis(2-methoxyethyl)amino]-,1-(2,6-dimethoxyphenyl)ester, 4-methyl ester.

[0225] To butanedioic, 2-[N-bis(2-methoxyethyl)amino]-, 4-methyl ester,sodium salt (13 g) was added 2,6-dimethoxyphenol (10.6 g),dichloromethane (100 ml), 4-dimethylaminopyridine (5.6 g), triethylamine(12.7 ml) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimidehydrochloride (13.1 g). The resulting suspension was stirred overnightand was then chromatographed on silica gel to give the title compound (2g, 11%) as a brown oil.

[0226] Positive ion ESI (M+H)⁺ 400.2

[0227] The following compound was prepared in a similar manner:

[0228] 24b: Butanedioic, 2-[N-bis(2-methoxyethyl)amino]-,1-(2,6-dimethoxy-4-methylphenyl)ester, 4-methyl ester: Positive ion ESI(M+H)⁺ 414.2

Example 25

[0229] Butanedioic acid, 2-(4-morpholinyl)-, 4-methyl ester, sodiumsalt.

[0230] A solution of maleic anhydride (25.3 g) in methanol (100 ml) washeated at reflux for 0.5 h with stirring. Once the reaction mixture hadcooled to room temperature morpholine (67.5 ml) was added andstirring-was continued for 1 h. To this mixture was added sodiumhydroxide (10.3 g) and the suspension was stirred for 1 h. The reactionmixture was concentrated under reduced pressure and the resulting solidwas filtered and washed with ethyl acetate (300 ml) to give the titlecompound (52.9 g, 86%).

[0231] Positive ion ESI (M+H)⁺ 218.2

Example 26

[0232] 26a: Butanedioic, 2-(4-morpholinyl)-,1-(2,6-dimethoxyphenyl)ester, 4-methyl ester.

[0233] To butanedioic acid, 2-(4-morpholinyl)-, 4-methyl ester, sodiumsalt (13 g) was added 2,6-dimethoxyphenol (8.0 g), chloroform (100 ml),4-dimethylaminopyridine (4.3 g), triethylamine (9.7 ml) and1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (10 g). Theresulting suspension was stirred overnight then chromatographed onsilica gel. The resulting solid was washed with petroleum ether (100 ml)to give the title compound (5 g, 41%) as a white solid. Positive ion ESI(M+H)⁺ 353.8

[0234] The following compound was prepared in a similar manner:

[0235] 26b: Butanedioic, 2-(4-morpholinyl)-,1-(2,6-dimethoxy-4-methylphenyl)ester, 4-methyl ester: Positive ion ESI(M+H)⁺ 368.0

Example 27

[0236] Butanedioic acid, 2-(1-piperidinyl)-, 4-methyl ester, sodiumsalt.

[0237] A solution of maleic anhydride (25.3 g) in methanol (100 ml) washeated at reflux for 0.5 h, with stirring, then was cooled to 0° C. withan ice/acetone bath. Piperidine (67.5 ml) was added and the reactionmixture was heated to 50° C. for 1 h. Sodium hydroxide (9.2 g) was addedand the suspension was stirred for 1 h. The reaction mixture wasconcentrated under reduced pressure and the resulting solid. wasfiltered and washed with ethyl acetate (300 ml) to give the titlecompound (43 g, 79%) as a white solid.

[0238] Positive ion ESI (M+H)⁺ 230.0

Example 28

[0239] 28a: Butanedioic, 2-(1-piperidinyl)-,1-(2,6-dimethoxyphenyl)ester, 4-methyl ester.

[0240] To butanedioic acid, 2-(1-piperidinyl)-, 4-methyl ester, sodiumsalt (10 g) was added 2,6-dimethoxyphenol (8.5 g), dichloromethane (100ml), 4-dimethylaminopyridine (5.2 g), triethylamine (11.7 ml) and1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (10.5 g).The resulting suspension was stirred overnight then chromatographed onsilica gel. The resulting solid was washed with diethyl ether (100 ml)to give the title compound (3.3 g, 22%) as a white solid. Positive ionESI (M+H)⁺ 352.0

[0241] The following compound was prepared in a similar manner.

[0242] 28b: Butanedioic, 2-(1-piperidinyl)-,1-(2,6-dimethoxy-4-methylphenyl)ester, 4-methyl ester: Positive ion ESI(M+H)⁺ 366

Example 29

[0243] Butanedioic acid, 2-(1-hexahydroazepinyl)-, 4-methyl ester,sodium salt.

[0244] A solution of maleic anhydride (20 g) in methanol (200 ml) washeated at reflux for 0.5 h, with stirring, then was cooled to 20° C.Hexamethyleneimine (67.5 ml) was added dropwise and the temperature wasmaintained at 20° C. After complete addition the reaction mixture wasstirred for 1 h at room temperature. Sodium hydroxide (8.2 g) was addedand stirring was continued for 1 h. The reaction mixture wasconcentrated under reduced pressure and dichloromethane (300 ml) wasadded. The suspension was filtered and the filtrate was concentratedunder reduced pressure to give the title compound (37 g, 72%) as anorange oil. Positive ion ESI (M+H)⁺ 230.0

Example 30

[0245] 30a: Butanedioic, 2-(1-hexahydroazepinyl)-,1-(2,6-dimethoxyphenyl)ester, 4-methyl ester.

[0246] To butanedioic acid, 2-(1-hexahydroazepinyl)-, 4-methyl ester,sodium salt (11.7 g) was added 2,6-dimethoxyphenol (9.3 g),dichloromethane (100 ml), 4-dimethylaminopyridine (5.7 g), triethylamine(13 ml) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride(11.6 g). The resulting mixture was stirred for 72 h thenchromatographed on silica gel to give the title compound (7.1 g, 42%) asa clear oil. Positive ion ESI (M+H)⁺ 365.6

[0247] The following compound was prepared in a similar manner:

[0248] 30b: Butanedioic, 2-(1-hexahydroazepinyl)-,1-(2,6-dimethoxy-4-methyl-phenyl)ester, 4-methyl ester: Positive ion ESI(M+H)⁺ 379.8

Example 31

[0249] Butanedioic, 4-(diethylamino)-4-oxo-, 2-(4-morpholinyl)-, sodiumsalt.

[0250] To a suspension of maleic anhydride (20 g) in dichloromethane(300 ml) at 0° C. was added a solution of diethylamine (19.4 ml) indichloromethane (100 ml). The reaction mixture was allowed to warm toroom temperature and concentrated under reduced pressure. Methanol (300ml) was added followed by morpholine (71.2 ml) and the resulting mixtureheated at reflux for 3 h. The reaction mixture was allowed to cool toroom temperature. Sodium hydroxide (8.16 g) was added and the suspensionstirred for 1 h. Concentration under reduced pressure gave an oil whichsolidified on stirring with petroleum ether (300 ml). The solid wasfiltered to give the title compound (47 g, 82%) as a white solid.Positive ion ESI (M+H)⁺ 259.0

Example 32

[0251] Butanedioic, 4-(diethylamino)-4-oxo-, 2-(4-morpholinyl)-,1-(2,6-dimethoxy4-methylphenyl)ester.

[0252] To butanedioic, 4-(diethylamino)4-oxo-, 2-(4-morpholinyl)-,sodium salt (10 g) was added 2,6-dimethoxy-4-methylphenol (7.8 g),chloroform (100 ml), 4-dimethylaminopyridine (0.5 g), triethylamine (10ml) and PyBroP (21.6 g). The resulting suspension was stirred overnightthen chromatographed on silica gel to give the title compound (5 g, 34%)as a white foam. Positive ion ESI (M+H)⁺ 409.4

Example 33

[0253] Butanedioic, 4-(1-piperidinyl)-4-oxo-, 2-(1-piperidinyl)-, sodiumsalt.

[0254] To a suspension of maleic anhydride (20 g) in dichloromethane(200 ml) at 0° C. was added a solution of piperidine (40.3 ml) indichloromethane (100 ml). The reaction mixture was allowed to warm toroom temperature and concentrated under reduced pressure. Methanol (200ml) was added followed by piperidine (40.3 ml) and the resulting mixtureheated at reflux for 3 h. The reaction mixture was allowed to cool toroom temperature. Sodium hydroxide (8.2 g) was added and the suspensionstirred for 1 h. Concentration under reduced pressure then stirring withdiethyl ether (300 ml) gave a solid which was filtered to give the titlecompound (34 g, 58%) as a white solid.

[0255] Positive ion ESI (M+H)⁺ 269.2

Example 34

[0256] 34a: Butanedioic, 4-(1-piperidinyl)-4-oxo-, 2-(1-piperidinyl)-,1-(2,6-dimethoxy-4-methylphenyl)ester.

[0257] To butanedioic, 4-(1-piperidinyl)-4-oxo-, 2-(1-piperidinyl)-,sodium salt (11.2 g) was added 2,6-dimethoxy-4-methylphenol (7.9 g),chloroform (150 ml), 4-dimethylaminopyridine (4.8 g), triethylamine(10.9 ml) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimidehydrochloride (9 g). The resulting suspension was stirred overnight thenchromatographed on silica gel to give the title compound (4 g, 24%) as aclear oil. Positive ion ESI (M+H)⁺ 419.2

[0258] The following compound was prepared in a similar manner:

[0259] 34b: Butanedioic, 4-(1-piperidinyl)-4-oxo-,2-(1-piperidinyl)-1-(2,6-dimethoxyphenyl)ester: Positive ion ESI (M+H)⁺405.4

Example 35

[0260] Butanedioic, 2-(1-hexahydroazepinyl)-4-oxo-4-(1-pyrrolidinyl)-,sodium salt.

[0261] To a suspension of maleic anhydride (24.4 g) in dichloromethane(300 ml) at 0° C. was added a solution of pyrrolidine (20.8 ml) indichloromethane (150 ml). The reaction mixture was allowed to warm toroom temperature and concentrated under reduced pressure. Methanol (250ml) was added followed by hexamethyleneimine (84.2 ml) and the resultingmixture heated at reflux for 3 h. The reaction mixture was allowed tocool to room temperature. Sodium hydroxide (9.96 g) was added and thesuspension heated at 60° C. for 1 h. Concentration under reducedpressure gave a solid which was stirred with diethyl ether (300 ml). Thesolid was filtered to give the title compound (57 g, 79%) as a whitesolid. Positive ion ESI (M+H)⁺ 269.0

Example 36

[0262] Butanedioic, 2-(1-hexahydroazepinyl)-4-oxo-4-(1-pyrrolidinyl)-,1-(2,6-dimethoxyphenyl)ester.

[0263] To butanedioic,2-(1-hexahydroazepinyl)-4-oxo-4-(1-pyrrolidinyl)-, sodium salt (11.4 g)was added 2,6-dimethoxyphenol (7.2 g), chloroform (150 ml),4-dimethylaminopyridine (4.8 g), triethylamine (10.9 ml) and1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (9 g). Theresulting suspension was stirred overnight then chromatographed onsilica gel. Recrystallisation from ethyl acetate gave the title compound(4.5 g, 28%) as white crystals.

[0264] Positive ion ESI (M+H)⁺ 405.4

Example 37

[0265] Butanoic acid, 2-bromo-4-(methylthio)-.

[0266] To a stirred solution of methionine (85.4 g) in water (792 ml)and hydrobromic acid (47% aqueous, 528 ml) at 0° C. was added a solutionof sodium nitrite (39.5 g) in water (100 ml). Stirring was continuedfor2 h at 0° C. and the reaction allowed to warm to room temperature andstand for 24 h. The aqueous phase was extracted with ethyl acetate (500ml), dried (sodium sulphate), filtered and concentrated under reducedpressure to give the title compound (33 g, 27%) as an orange oil.

[0267]¹H NMR (CDCl₃); δ2.11 (3H, s), 2.17-2.42 (2H, m), 2.58-2.70 (2H,m), 4.88-4.45 (1H, m)

Example 38

[0268] 38a: Butanoic acid, 2-bromo-4-(methylthio),1-(2,6-dimethoxyphenyl)ester.

[0269] To a solution of butanoic acid, 2-bromo-4-(methylthio)-(33 g) andpyridine (0.5 ml) in dichloromethane (50 ml) was added a solution ofoxalyl chloride (27 ml) in dichloromethane (50 ml). The reaction mixturewas stirred. for 24 h and concentrated under reduced pressure. To thissolution was added dichloromethane (100 ml) and 2,6-dimethoxyphenol(23.9 g) and the reaction mixture was cooled to 0° C. A solution oftriethylamine (43 ml) in dichloromethane (50 ml) was then added.dropwise. After complete addition the reaction mixture was allowed towarm to room temperature and stirred for 2 h. Concentration underreduced pressure and chromatography on silica gel gave the titlecompound (25.8 g, 48%) as an orange oil.

[0270]¹H NMR (CDCl₃); δ2.15 (s, 3H), 2.33-2.43 (m, 1H), 2.48-2.58 (m,1H), 2.72-2.79 (m, 2H), 3.82 (s, 6H), 4.71-4.75 (t, 1H), 6.60 (d, 2H),7.02 (t, 1H)

[0271] The following compound was prepared in a similar manner:

[0272] 38b: Butanoic acid, 2-bromo-4-(methylthio),1-(2,6-dimethoxy-4-methylphenyl)ester.

[0273]¹H NMR (CDCl₃); δ2.14 (s, 3H), 2.33 (s, 3H), 2.36-2.45 (m, 1H),2.50-2.58 (m, 1H), 2.72-2.76 (m, 2H), 3.79 (s, 6H), 4.71 (t, 1H), 6.41(s, 2H)

Example 39

[0274] 39a: Butanoic acid, 4-(methylthio)-2-(4-morpholinyl)-,1-(2,6-dimethoxy-4-methylphenyl)ester.

[0275] Butanoic acid, 2-bromo-4-(methylthio),1-(2,6-dimethoxy-4-methylphenyl)ester (5.4 g) and morpholine (5.2 ml)were heated at 35° C. for 2 h. Chromatography on silica gel gave thetitle compound (1 g, 19%) as an oil.

[0276] Positive ion ESI (M+H)⁺ 353.8

[0277] The following compounds were prepared in a similar manner:

[0278] 39b: Butanoic acid, 4-(methylthio)-2-(1-pyrrolidinyl)-,1-(2,6-dimethoxy-4-methylphenyl)ester: Positive ion ESI (M+H)⁺ 353.8

[0279] 39c: Butanoic acid,2-[N-bis(2-methoxyethyl)amino]-4-(methylthio),1-(2,6-dimethoxy-4-methylphenyl)ester: Positive ion ESI (M+H)⁺ 416.2

Example 40

[0280] 40a: Butanoic acid, 4-(methylthio)-2-(1-piperidinyl)-,1-(2,6-dimethoxyphenyl)ester.

[0281] Butanoic acid, 2-bromo-4-(methylthio),1-(2,6-dimethoxyphenyl)ester (5 g) and piperidine (5.2 ml) were stirredtogether for 1 h. Chromatography on silica gel gave the title compound(1.3 g, 26%) as a solid.

[0282] Positive ion ESI (M+H)⁺ 353.8

[0283] The following compounds were prepared in a similar manner:

[0284] 40b: Butanoic acid, 4-(methylthio)-2-(1-pyrrolidinyl)-,1-(2,6-dimethoxyphenyl)ester: Positive ion ESI (M+H)⁺ 339.4

[0285] 40c: Butanoic acid, 2-(1-hexahydroazepinyl)-4-(methylthio),1-(2,6-dimethoxyphenyl)ester: Positive ion ESI (M+H)⁺ 367.8

[0286] 40d: Butanoic acid, 2-(1-hexahydroazocinyl)-4-(methylthio),1-(2,6-dimethoxyphenyl)ester: Positive ion ESI (M+H)⁺ 382.2

Example 41

[0287] Butanoic acid, 2-bromo-4-(methylsulphonyl)-

[0288] To a stirred solution of methionine (42.7 g) in water (396 ml)and hydrobromic acid (47% aqueous, 264 ml) at 0° C. was added a solutionof sodium nitrite (63.2 g) in water (200 ml). Stirring was continued for2 h at 0° C. and then the reaction was allowed to warm to roomtemperature and stand for 24 h. After addition of sodium metabisulphite(10 g), the aqueous phase was extracted with ethyl acetate (500 ml),dried (sodium sulphate), filtered and concentrated under reducedpressure to give the title compound (33 g, 47%) as a pale yellow solid.Negative ion ESI (M−H)⁻ 244.6

Example 42

[0289] Butanoic acid, 2-bromo-4-(methylsulphonyl),1-(2,6-dimethoxy-4-methylphenyl)ester.

[0290] To a solution of butanoic acid, 2-bromo-4-(methylsulphonyl)-(5.4g) and pyridine (0.2 ml) in dichloromethane (50 ml) was added oxalylchloride (3.9 ml). The reaction mixture was stirred for 24 h andconcentrated under reduced pressure. To this mixture was addeddichloromethane (50 ml) and 2,6-dimethoxy-4-methylphenol (4.8 g).Triethylamine (6.1 ml) was then added dropwise. After complete additionthe reaction mixture was allowed to stir for 2 h. Chromatography onsilica gel gave the title compound (7 g, 80%) as a solid. Negative ionESI (M−H)³¹ 394.4

Example 43

[0291] Butanoic acid,4-(methylsulphonyl)-2-(1-[1,2,3,6-tetrahydropyridinyl])-,1-(2,6-dimethoxy-4-methylphenyl)ester.

[0292] Butanoic acid, 2-bromo-4-(methylsulphonyl),1-(2,6-dimethoxy-4-methylphenyl)ester (3.2 g) and1,2,3,6-tetrahydropyridine (3 ml) were stirred together for 2 h.Chromatography on silica gel gave the title compound (1 g, 31%) a solid.Positive ion ESI (M+H)⁺ 398.0

Example 44

[0293] 2-Bromopentane-1,5-dioic acid, mono-5-methyl ester.

[0294] An aqueous solution of sodium nitrite (10.5 g, 0.15 mol in 25 mlH₂O) was added dropwise to a stirred solution of L-glutamate 5-methylester (8.06 g, 0.05 mol) in aqueous HBr (47%, 47 ml) and water (70 ml)cooled to −5° C. in an ice/acetone bath. The sodium nitrite solution wasadded over 1 h with care being taken to maintain the temperature at <0°C. After an additional 1 h, the aqueous solution was washed withdiethylether (3×150 ml). The combined organic phase was then washed withsaturated sodium metabisulfite solution (2×75 ml) until the brominecolour was removed. The organic phase was dried (Na₂SO₄), filtered andsolvent removed to give the title compound as a yellow oil (7.47 g,66.4%).

[0295]¹H NMR (CDCl₃): δ4.47-4.40 (m, 1H), 3.70 (s, 3H), 2.60-2.54 (m,2H), 2.47-2.37 (m, 1H), 2.37-2.24 (m, 1H).

Example 45

[0296] 2-Bromopentan-1-oylchloride, mono-5-methyl ester.

[0297] Oxalyl chloride (12.21 ml, 0.14 mol) was added dropwise over 1 hunder nitrogen to a stirred solution of 2-bromopentane-1,5-dioic acid,mono-5-methyl ester (15.86 g, 0.07 mol) in dichloromethane (300 ml) andpyridine (3 drops), cooled in an ice bath. The reaction was allowed towarm slowly to room temperature and stirring continued overnight. After17 h ¹H nmr showed that the reaction was incomplete so more oxalylchloride (8.00 ml, 1.31 eq.) was added. After 22 h, the solvent wasremoved in vacuo to give the title compound as a yellow oil (19.08 g,100%). This intermediate was used directly without further purification.

[0298]¹H NMR (CDCl₃): δ4.72 (dd, 1H), 3.72 (s, 3H), 2.60-2.45 (m, 3H),2.37-2.28 (m, 1H)

Example 46

[0299] 46a: Pentanedioic acid, 2-bromo-, 1-(2,6-dimethoxyphenyl)ester,5-methyl ester.

[0300] Triethylamine (14.17 ml, 0.10 mol) was added slowly, undernitrogen, to a stirred solution of 2-bromopentan-1-oylchloridemono-5-methyl ester (12.00 g, 0.046 mol) and 2,6-dimethoxyphenol (8.55g, 0.055 mol) in dichloromethane (100 ml) cooled in an ice bath. Thesystem was then allowed to warm to room temperature and stirringcontinued for 6 h whereupon solvent was removed in vacuo. The residuewas dissolved in water (50 ml) and extracted with diethylether (2×200ml). The combined organic phase was dried (Na₂SO₄), filtered and thesolvent removed to give the crude product as a dark brown oil. This waspurified by chromatography on alumina (pet. ether:EtOAc, 2:1) to givethe title compound as a clear oil (12.96 g, 77.7%).

[0301]¹H NMR (CDCl₃): δ7.14 (dd, 1H), 6.60 (d, 2H), 4.65 (dd, 1H), 3.82(s, 6H), 3.72 (s, 3H), 2.68-2.62 (m, 2H), 2.61-2.42 (m, 2H).

[0302] The following compound was prepared in a similar manner:

[0303] 46b: Pentanedioic acid, 2-bromo-,1-(2,6-dimethoxy-4-methylphenyl)ester, 5-methyl ester.

[0304]¹H NMR (CDCl₃): δ6.41 (2H, s), 4.63 (1H, dd), 3.79 (6H, s), 3.71(3H, s), 2.69-2.62 (2H, m), 2.62-2.40 (2H, m), 2.34 (3H, s).

Example 47

[0305] 47a: Pentanedioic acid, 2-(1-piperidinyl)-,1-(2,6-dimethoxyphenyl)ester, 5-methyl ester hydrochloride (1:1) salt.

[0306] Piperidine (1.69 ml, 0.017 mol) and pentanedioic acid, 2-bromo-,1-(2,6-dimethoxyphenyl)ester, 5-methyl ester (2.06 g, 5.71 mmol) werestirred together neat at room temperature for 18 h. Chromatography ofthe residue on alumina (pet. ether:ethyl acetate 4:1) gave the desiredproduct as a clear oil (0.61 g, 29%). Hydrogen chloride gas was bubbledthrough a solution of the product in diethylether and the whiteprecipitate that formed was collected by filtration and dried undervacuum (0.48 g).

[0307]¹H NMR (CDCl₃+Na₂CO₃): δ1.53-1.43 (m, 2H), 1.68-1.53 (m, 4H), 2.15(q, 2H), 2.59-2.46 (m, 2H), 2.68-2.59 (m, 2H), 2.88-2.79 (m, 2H), 3.47(dd, 1H), 3.70 (s, 3H), 3.81 (s, 6H), 6.60 (d, 2H), 7.10 (dd, 1H).

[0308] Positive ion ESI (M+H)⁺ 366; ν/cm (KBr) 3440, 2950, 2319, 1758,1731, 1609, 1482.

[0309] The following compounds were prepared in a similar manner:

[0310] 47b: Pentanedioic acid, 2-(1-hexahydroazepinyl)-,1-(2,6-dimethoxyphenyl)ester, 5-methyl ester hydrochloride (1:1) salt.

[0311]¹H NMR (CDCl₃+Na₂CO₃): δ1.74-1.52 (m, 8H), 2.27-2.03 (m, 2H), 2.58(dd, 2H), 2.84-2.72 (m, 2H), 3.05-2.95 (m, 2H), 3.60 (dd, 1H), 3.70 (s,3H), 3.80 (s, 6H), 6.60 (d, 2H), 7.10 (dd, 1H).

[0312] Positive ion ESI (M+H)⁺ 380

[0313] ν/cm (KBr) 3440, 2936, 2423, 1760, 1732, 1608, 1483.

[0314] 47c: Pentanedioic acid, 2-(N-thiomorpholinyl)-,1-(2,6-dimethoxyphenyl)ester, 5-methyl ester hydrochloride (1:1) salt

[0315]¹H NMR (CDCl₃+Na₂CO₃): δ2.20-2.11 (m, 2H), 2.60-2.42 (m, 2H),2.76-2.60 (m, 4H), 3.00-2.90 (m, 2H), 3.23-3.14 (m, 2H), 3.49 (dd, 1H),3.70 (s, 3H), 3.83 (s, 6H), 6.60 (d, 2H), 7.12 (dd, 1H).

[0316] Positive ion ESI (M+H)⁺ 384

[0317] ν/cm (KBr) 2962, 2298, 1761, 1728, 1610, 1484.

Example 48

[0318] 48a: Pentanedioic acid, 2-[bis-(2-methoxyethyl)amino]-,1-(2,6-dimethoxyphenyl)ester, 5-methyl ester hydrochloride (1:1) salt.

[0319] Bis-(2-methoxyethyl)amine (2.53 ml, 0.017 mol) and pentanedioicacid, 2-bromo-, 1-(2,6-dimethoxyphenyl)ester, 5-methyl ester (2.06 g,5.71 mmol) were stirred together neat at room temperature for 18 h andthen at 60° C. for a further 6 h. The residue was dissolved indichloromethane and extracted with 1M HCl. The aqueous phase was thenneutralised using solid sodium bicarbonate and the solution wasextracted with diethylether (3×100 ml). The combined organic layer wasdried (Na₂SO₄), filtered and the solvent removed in vacuo.Chromatography of the residue on alumina (pet. ether:ethyl acetate, 3:1)gave the desired product as a clear oil (1.63 g, 69%). Hydrogen chloridegas was bubbled through a solution of the product in diethylether andthe white precipitate that formed was collected by filtration and driedunder vacuum (1.12 g). ¹H NMR (CDCl₃+Na₂CO₃): δ2.11-2.00 (m, 1H)2.31-2.19 (m, 1H), 2.69-2.52 (m, 2H), 3.02-2.94 (m, 4H), 3.35 (s, 6H),3.52-3.39 (m, 4H), 3.70 (s, 3H), 3.79-3.74 (m, 1H), 3.80 (s, 6H), 6.60(d, 2H), 7.11 (dd, 1H).

[0320] Positive ion ESI (M+H)⁺ 414

[0321] ν/cm (KBr) 3430, 2944, 2139, 1749, 1739, 1619, 1485.

Example 49

[0322] 49a: Pentanedioic acid, 2-(1-pyrrolidinyl)-,1-(2,6-dimethoxy4-methylphenyl)-ester, 5-methyl ester hydrochloride(1:1) salt.

[0323] Pyrrolidine (1.23 ml, 0.015 mol) and pentanedioic acid, 2-bromo-,1-(2,6-dimethoxy-4-methylphenyl)ester, 5-methyl ester (1.85 g, 4.93mmol) were stirred together at room temperature for 18 h. Chromatographyon alumina (pet. ether:ethyl acetate, 2:1) gave the desired product as aclear oil (0.35 g, 19.4%). Hydrogen chloride gas was bubbled through asolution of the product in diethylether and the white precipitate thatformed was collected by filtration and dried under vacuum (0.22 g).

[0324]¹H NMR (CDCl₃+Na₂CO₃): δ1.88-1.78 (m, 4H) 2.28-2.20 (m, 2H), 2.33(s, 3H), 2.70-2.49 (m, 2H), 2.86-2.78 (m, 4H), 3.48 (dd, 1H), 3.69 (s,3H), 3.77 (s, 6H), 6.41 (s, 2H).

[0325] Positive ion ESI (M+H)⁺ 366

[0326] ν/cm (KBr) 3397, 2944, 2586, 1767, 1739, 1605, 1506, 1418.

[0327] The following compounds were prepared in a similar manner:

[0328] 49b: Pentanedioic acid, 2-(1-piperidinyl)-,1-(2,6-dimethoxy-4-methylphenyl)ester, 5-methyl ester hydrochloride(1:1) salt.

[0329]¹H NMR (CDCl₃+Na₂CO₃): δ1.67-1.42 (m, 6H), 2.21-2.12 (m, 2H), 2.33(s, 3H), 2.59-2.46 (m, 2H), 2.67-2.59 (m, 2H), 2.86-2.78 (m, 2H), 3.44(dd, 1H), 3.69 (s, 3H), 3.78 (s, 6H), 6.41 (s, 2H).

[0330] Positive ion ESI (M+H)⁺ 380

[0331] ν/cm (KBr) 3440, 2923, 2246, 1755, 1732, 1605, 1506, 1455.

[0332] 49c: Pentanedioic acid, 2-(N-thiomorpholinyl)-,1-(2,6-dimethoxy-4-methylphenyl)ester, 5-methyl ester hydrochloride(1:1) salt.

[0333]¹H NMR (CDCl₃+Na₂CO₃): δ2.17-2.08 (m, 2H), 2.34 (s, 3H), 2.58-2.42(m, 2H), 2.74-2.60 (m, 4H), 2.98-2.89 (m, 2H), 3.21-3.12 (m, 2H),3.50-3.42 (m, 1H), 3.70 (s, 3H), 3.80 (s, 6H), 6.42 (s, 2H).

[0334] Positive ion ESI (M+H)⁺ 398

[0335] ν/cm (KBr) 3444, 2949, 2253, 1764, 1736, 1606, 1507, 1467.

Example 50

[0336] Pentanedioic acid, 2-[N-bis(2-ethoxyethyl)amino)]-,1-(2,6-dimethoxy-4-methylphenyl)ester, 5-methyl ester hydrochloride(1:1) salt.

[0337] Bis(2-ethoxyethyl)amine (2.90 ml, 0.017 mol) and pentanedioicacid, 2-bromo-, 1-(2,6-dimethoxy4-methylphenyl)ester, 5-methyl ester(2.00 g, 5.33 mmol) were stirred together neat at room temperature for18 h and then at 60° C. for a further 4 h. Chromatography of the residueon alumina (pet. ether:ethyl acetate, 3:1) gave the desired product as aclear oil (1.45 g, 60%). Hydrogen chloride gas was bubbled through asolution of the product in diethylether and the white precipitate thatformed was collected by filtration and dried under vacuum (1.05 g).

[0338]¹H NMR (CDCl₃+Na₂CO₃): δ1.20 (t, 6H), 2.12-2.01 (m, 1H), 2.28-2.17(m, 1H), 2.33 (s, 3H), 2.72-2.51 (m, 2H), 3.01-2.94 (m, 4H), 3.54-3.44(m, 8H), 3.69 (s, 3H), 3.76-3.71 (m, 1H), 3.77 (s, 6H), 6.40 (s, 2H).

[0339] Positive ion ESI (M+H)⁺ 456

[0340] ν/cm (KBr) 3443, 2970, 2127, 1759, 1732, 1604, 1507, 1464.

Example 51

[0341] 51a: (ξ)-2-[4-(Hexahydro-1-oxazepinyl)]-4-methoxybutyricacid,2,6-dimethoxyphenyl ester.

[0342] The racemic 2-[4-(hexahydro-1-oxazepinyl)]-4-methoxybutyric acid,2,6-dimethoxyphenyl ester, described previously, was resolved via chiralpreparative chromatography on a Chiracel OJ column (2 cm×25 cm, Daicel)using isohexane-isopropanol (97:3 v/v) as the eluent. The title compoundeluted second. Positive Ion ESI (M+H)⁺ 354.1

[0343] The following compounds were prepared in a similar manner. Insome instances a different ratio of isohexane to isopropanol was usedand diethylamine (HPLC grade) could also be added (0.1%).

[0344] 51b: (ξ)-2-[4-(Hexahydro-1-oxazepinyl)]-4-methoxybutyricacid,2,6-dimethoxyphenyl ester. (1^(st) to elute)

[0345] Positive Ion ESI (M+H)⁺ 354.1

[0346] 51c: (ξ)-2-[N-Bis(2-methoxyethyl)amino]-3-methoxypropionic acid,2,6-dimethoxy-4-methylphenyl ester. (1^(st) to elute)

[0347] Positive Ion ESI (M+H)⁺ 386.4

[0348] 51d: (ξ)-2-[N-Bis(2-methoxyethyl)amino]-3-methoxypropionic acid,2,6-dimethoxy-4-methylphenyl ester. (2_(nd) to elute)

[0349] Positive Ion ESI (M+H)⁺ 386.4

[0350] 51e: (ξ)-3-(4-Morpholinyl)-2-(N-thiomorpholinyl)propanoic acid,2,6-dimethoxyphenyl ester. (1_(st) to elute)

[0351] Positive Ion ESI (M+H)⁺ 397.0

[0352] 51f: (ξ)-3-(4-Morpholinyl)-2-(N-thiomorpholinyl)propanoic acid,2,6-dimethoxyphenyl ester. (2^(nd) to elute); Positive Ion ESI (M+H)⁺397.0

Example 52

[0353] 52a: 2R-[4-(Hexahydro-1-oxazepinyl)]-3-methoxypropionic acid,2,6-dimethoxyphenyl ester.

[0354] The racemic 2-[4-(hexahydro-1-oxazepinyl)]-3-methoxypropionicacid, 2,6-dimethoxyphenyl ester ,described previously, (30 g, 88 mmol)was dissolved in ethyl acetate and a solution of di-p-toluoyl-R-tartaricacid in ethyl acetate (300 ml) added. When crystallisation was completethe salt was filtered off, washed and dried (20.3 g). This salt wasconverted to the free base using sodium bicarbonate solution and ethylacetate giving the free base as a clear oil (9.6 g). Analysis by liquidchromatography (Chiracel OJ) as described previously showed 82% of therequired isomer (second to elute). This process was then repeated on thepartly purified base, until after three further treatments analysisshowed 99% of the required isomer (4.85 g).

[0355] Positive ion ESI (M+H)⁺ 339.9

[0356] The following compound was prepared in a similar manner usingdi-p-toluoyl-S-tartaric acid:

[0357] 52b: 2S-[4-(Hexahyro-1-oxazepinyl)]-3-methoxypropionic acid,2,6-dimethoxyphenyl ester (1^(st) to elute)

[0358] Positive ion ESI (M+H)⁺ 339.9

[0359] The following enantiomers were prepared in a similar manner:

[0360] 52c: (ξ)-2-[4-(Hexahydro-1-oxazepinyl)]-3-ethoxypropionic acid,2,6-dimethoxyphenyl ester (2^(nd) isomer to elute)

[0361] Positive ion ESI (M+H)⁺ 353.7

[0362] 52d: (ξ)-2-[4-Hexahydro-1-oxazepinyl)]-3-ethoxypropionic acid,2,6-dimethoxyphenyl ester (1^(st) isomer to elute)

[0363] Positive ion ESI (M+H)⁺ 353.7

Example 53

[0364] 2-[4-(Hexahydro-1-oxazepinyl)]-3-methoxypropionic acid,2,6-dimethoxyphenyl ester hydrochloride (1:1) salt.

[0365] Hydrogen chloride gas was passed through a solution of2-[4-(hexahydro-1-oxazepinyl)]-3-methoxypropionic acid,2,6-dimethoxyphenyl ester (0.7 g) in anhydrous dichloromethane for 1-2minutes. Most of the dichloromethane was then removed under reducedpressure and the hydrochloride salt precipitated by the addition of drydiethyl ether. The resulting white solid was filtered off and washedwith diethyl ether to give the title compound (0.7 g, 90%). ¹H NMR(CDCl₃+sodium carbonate): δ1.85-2.02 (m, 2H), 2.95-3.04 (m, 2H),3.05-3.17 (m, 2H), 3.43 (s, 3H), 3.67-3.87 (m, 12H), 3.93 (t, 1H), 6.60(d, 2H), 7.13 (t, 1H). Positive Ion ESI (M+H)⁺ 339.9

Example 54

[0366] 54a: 2R-[4-(Hexahydro-1-oxazepinyl)]-3-methoxypropionicacid,2,6-dimethoxyphenyl ester hydrobromide (1:1) salt.

[0367] 2R-[4-(Hexahydro-1-oxazepinyl)]-3-methoxypropionic acid,2,6-dimethoxyphenyl ester (4.75 g) was dissolved in dry diethyl etherand hydrogen bromide gas bubbled in with cooling till a slight excesswas present. The crystals were filtered off, washed and dried to givethe title compound (5.57 g). A sample was crystallised from a mixture ofmethanol and isopropanol to give a single crystal. X-ray crystalstructure analysis showed this to be the RR isomer.

[0368]¹H NMR (CDCl₃+sodium carbonate) δ1.85-1.99 (m, 2H), 2.95-3.02 (m,2H), 3.02-3.16 (m, 2H), 3.43 (s, 3H), 3.81 (s, 6H), 3.70-3.92 (m, 7H),6.60 (d, 2H), 7.11 (t, 1H). Positive ion ESI (M+H)⁺ 339.6

[0369] The following compound was prepared in a similar manner:

[0370] 54b: 2S-[4-(Hexahydro-1-oxazepinyl)]-3-methoxypropionic acid,2,6-dimethoxyphenyl ester hydrobromide 1;1 salt.

[0371]¹H NMR (CDCl₃) δ1.85-1.99 (m, 2H), 2.95-3.02 (m, 2H), 3.02-3.16(m, 2H), 3.43 (s, 3H), 3.81 (s, 6H), 3.70-3.92 (m, 7H), 6.60 (d, 2H),7.11 (t, 1H); Positive ion ESI (M+H)⁺ 339.7

Example 55 HYPNOTIC ACTIVITY

[0372] The hypnotic potency of the alanine 2,6-dialkoxyphenyl esterderivatives of the invention was determined upon their intravenousadministration in mice. The dose required to cause a loss of rightingreflex for a minimum period of 30 seconds in 50% of treated mice afterintravenous injection over 10 seconds was determined. This dose istermed the HD₅₀ (hypnotic dose ₅₀) and is expressed in μmol.kg⁻¹. Thesein vivo experiments were carried out as described in detail by Andersonet al., J. Med. Chem. 1997, 40, 1668-1681. The in vivo HD₅₀ data for anumber of compounds of the invention are given in Table I.

[0373] The in vitro effect of the compounds of the invention at GABA_(A)receptors was assessed through determination of their ability to inhibit[³⁵S]-TBPS ([³⁵S]-tert-butyl bicyclophosphorothionate) binding to ratwhole brain membranes. The concentration of alanine 2,6-dialkoxyphenylester derivative required to inhibit 50% of binding of [³⁵S]-TBPS, i.e.the IC₅₀, was determined. These in vitro experiments were carried out asdescribed in detail by Anderson et al., J. Med. Chem. 1997, 40,1668-1681. TABLE 1 Hypnotic Activity Ex- HD50 HD50 HD50 HD50 am- μmol ·Ex- μmol · Ex- μmol · Ex- μmol · ple¹ kg⁻¹ ample kg⁻¹ ample kg⁻¹ amplekg⁻¹  3a 30 10h 27 19g 15 40b 40  3b 41 10i 36 19h 21 40c 18  3c 21 10j25 19i 19 40d 35  3d 22 10k 34 19j 21 43 39  3f 46 10l 26 19k 15 47a 50 3g 25 10m 25 20b 24 47b 36  3i 28 10n 38 21a 50 47c 44  3j 42 10o 3621b 25 48 37  3l 58 10p 23 24a 48 49a 50  3m 31 10q 25 24b 48 49b 47  3n34 10r 27 26b 46 50 40  3p 46 10s 47 28a 26 51a 15  3q 23 10t 36 28b 4851b 30  3r 20 10u 17 30a 23 51c 24  4a 28 10v 41 30b 26 51d 36 10a 1510w 26 32a 38 52a 16 10b 38 18a 15 34a 38 52b 40 10c 22 18b 31 34b 3910d 21 18c 31 36 34 10e 17 19a 17 39a 35 10f 22 19b 29 39b 31 10g 28 19c28 39c 23 19d 27 40a <26 19e 27 19f 21

1. An alanine 2,6-dialkoxyphenyl ester derivative having the generalformula I

wherein R₁ is (C₁₋₃)alkyloxy, (C₁₋₃)alkyloxy(C₁₋₃)alkyl,(C₁₋₃)alkylthio, (C₁₋₃)alkylthio-(C₁₋₃)alkyl, (C₁₋₃)alkylsulfinyl,(C₁₋₃)alkylsulfinyl(C₁₋₃)alkyl, (C₁₋₃)alkylsulfonyl,(C₁₋₃)alkylsulfonyl(C₁₋₃)alkyl, (C₁₋₃)alkyloxycarbonyl,(CH₂)_(n)—CO—NR₈R₉ or (CH₂)_(n)—NR₈R₉; n is 0, 1 or 2; R₂ is hydrogen or(C₁₋₃)alkyl; R₃ is (C₁₋₃)alkyl or (C₁₋₃)alkyloxy(C₁₋₃)alkyl; R₄ is(C₁₋₃)alkyloxy(C₁₋₃)alkyl; or R₃ and R₄ form together with the nitrogenatom to which they are bound a 5-, 6-, or 7-membered ring, optionallycontaining a further heteroatom selected from O and S, and which ringmay optionally contain a double bond and be optionally substituted with(C₁₋₃)alkyl or (C₁₋₃)alkyloxy; R₅ and R₆ are independently (C₁₋₃)alkyl;R₇ is hydrogen, (C₁₋₃)alkyl, (C₁₋₃)alkyloxy or (C₂₋₃)alkenyl; R₈ and R₉are independently (C₁₋₃)alkyl; or R₈ and R₉ form together with thenitrogen atom to which they are bound a 5-, 6-, or 7-membered,optionally containing a further heteroatom selected from O and S, andwhich ring may optionally contain a double bond; or a pharmaceuticallyacceptable salt thereof.
 2. The alanine 2,6-dialkoxyphenyl esterderivative of claim 1, wherein R₅ and R₆ are methyl.
 3. The alanine2,6-dialkoxyphenyl ester derivative of claim 1 or 2, wherein R₃ and R₄form together with the nitrogen atom to which they are bound a 5-, 6- or7-membered ring, optionally containing a further heteroatom selectedfrom O and S, and which ring may optionally contain a double bond and beoptionally substituted with (C₁₋₃)alkyl or (C₁₋₃)alkyloxy.
 4. Thealanine 2,6-dialkoxyphenyl ester derivative of claim 3, wherein R₁ is(C₁₋₃)alkyloxy or (C₁₋₃)alkyloxy(C₁₋₃)alkyl.
 5. The alanine2,6-dialkoxyphenyl ester derivative of claim 4, wherein the α-carbonatom is that of the R-enantiomer.
 6. An alanine 2,6-dialkoxyphenyl esterderivative having the general formula I of claim 1 for use in therapy.7. A pharmaceutical composition comprising an alanine 2,6-dialkoxyphenylester derivative having the general formula I, or a pharmaceuticallyacceptable salt thereof, in admixture with pharmaceutically acceptableauxiliaries.
 8. The use of an alanine 2,6-dialkoxyphenyl esterderivative having the general formula I, or a pharmaceuticallyacceptable salt thereof, for the manufacture of a medicament havinghypnotic activity.
 9. The use of an alanine 2,6-dialkoxyphenyl esterderivative having the general formula I, or a pharmaceuticallyacceptable salt thereof, for the manufacture of a medicament havingsedative or analgesic activity, or for the treatment of GABA relateddiseases, such as anxiety, stress, sleep disorders, post nataldepression, and premenstrual tension, and in the alleviation of seizure.